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Background: RASopathies are genetic syndromes that result from pathogenic variants in the RAS-MAPK cellular signaling pathway. These syndromes, which include neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome, are associated with a complex array of medical and behavioral health complications. Despite a heightened risk for social challenges and autism spectrum disorder (ASD), few studies have compared different aspects of social behavior across these conditions. It is also unknown whether the underlying neuropsychological characteristics that contribute to social competence and socially empathetic ("prosocial") behaviors differ in children with RASopathies as compared to children with nonsyndromic (i.e., idiopathic) ASD. Methods: In this cross-sectional, survey-based investigation, caregivers of preschool and school-aged children with RASopathies (n = 202) or with idiopathic ASD (n = 109) provided demographic, medical, and developmental information about their child, including psychiatric comorbidities. For children who were able to communicate verbally, caregivers also completed standardized rating scales to assess social competence and empathetic behavior as well as symptoms of hyperactivity/inattention and emotional problems. Results: As compared to children with idiopathic ASD, children with RASopathies were rated as demonstrating more resilience in the domain of empathy relative to their overall social competence. Similarities and differences emerged in the psychological factors that predicted social behavior in these two groups. Stronger communication skills and fewer hyperactive-impulsive behaviors were associated with increased empathy and social competence for both groups. Greater emotional challenges were associated with lower social competence for children with RASopathies and stronger empathy for children with idiopathic ASD. Among children with RASopathy and a co-occurring ASD diagnosis, socially empathetic behaviors were observed more often as compared to children with idiopathic ASD. Conclusions: Findings suggest that the development of social behavior among children with RASopathies involves a distinct pattern of strengths and weaknesses as compared to a behaviorally defined disorder (idiopathic ASD). Identification of areas of resilience as well as behavioral and social challenges will support more targeted intervention. [ABSTRACT FROM AUTHOR]

RASopathies are a group of syndromes caused by germline mutations of the RAS/MAPK pathway. They include Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, and Noonan syndrome with multiple lentigines, which share many characteristic features including cardiac abnormalities. Here, we retrospectively reviewed the clinical manifestations and evaluated the genotype-phenotype associations with special focus on cardiac lesions of the patients with RASopathies. Cardiac symptoms were the most common initial presentation (27 %), except for admission to neonatal intensive care. Although there was a significant gap between the first visit to the hospital and the diagnosis of the genetic syndrome (19.9 ± 39.1 months), the age at the clinical diagnosis of the genetic syndrome was significantly lower in patients with CHD than in patients without CHD (47.26 ± 67.42 vs. 86.17 ± 85.66 months, p = 0.005). A wide spectrum of cardiac lesions was detected in 76.1 % (118/155) of included patients. The most common lesion was pulmonary stenosis, followed by atrial septal defect and hypertrophic cardiomyopathy (HCMP). About half of the pulmonary stenosis and HCMP patients progressed during the median follow-up period of 109.9 (range 9.7-315.4) months. Early rapid aggravation of cardiac lesions was linked to poor prognosis. MEK1, KRAS, and SOS1 mutations tend to be highly associated with pulmonary stenosis. Cardiologists may play important roles in early detection and diagnosis of RASopathies as well as associated CHDs. Due to the variety of clinical presentations and their progression of severity, proper management with regular long-term follow-up of these patients is essential. [ABSTRACT FROM AUTHOR]

Synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) is considered to be the neurophysiological correlate of learning and memory. Impairments are discussed to be one of the underlying pathophysiological mechanisms of developmental disorders. In so-called RASopathies [e.g., neurofibromatosis 1 (NF1)], neurocognitive impairments are frequent and are affected by components of the RAS pathway which lead to impairments in synaptic plasticity. Transcranial magnetic stimulation (TMS) provides a non-invasive method to investigate synaptic plasticity in humans. Here, we review studies using TMS to evaluate synaptic plasticity in patients with RASopathies. Patients with NF1 and Noonan syndrome (NS) showed reduced cortical LTP-like synaptic plasticity. In contrast, increased LTP-like synaptic plasticity has been shown in Costello syndrome. Notably, lovastatin normalized impaired LTP-like plasticity and increased intracortical inhibition in patients with NF1. TMS has been shown to be a safe and efficient method to investigate synaptic plasticity and intracortical inhibition in patients with RASopathies. Deeper insights in impairments of synaptic plasticity in RASopathies could help to develop new options for the therapy of learning deficits in these patients. [ABSTRACT FROM AUTHOR]

Background:Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.Methods:We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.Results:We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.Conclusions:These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours. [ABSTRACT FROM AUTHOR]

Costello syndrome is a pediatric genetic disorder linked to oncogenic germline mutations in the HRAS gene. The disease is characterized by multiple developmental abnormalities, as well as predisposition to malignancies. Our recent observation that heart tissue from patients with Costello syndrome showed a loss of the glycosaminoglycan chondroitin-4-sulfate (C4S) inspired our present study aimed to explore a functional involvement of the chondroitin sulfate (CS) biosynthesis gene Carbohydrate sulfotransferase 11/Chondroitin-4-sulfotransferase-1 (CHST11/C4ST-1), as well as an impaired chondroitin sulfation balance, as a downstream mediator of oncogenic HRAS in Costello syndrome. Here we demonstrate a loss of C4S, as well as a reduction in C4ST-1 mRNA and protein expression, in primary fibroblasts from Costello syndrome patients. We go on to show that expression of oncogenic HRAS in normal fibroblasts can repress C4ST-1 expression, whereas interference with oncogenic HRAS signaling in Costello syndrome fibroblasts elevated C4ST-1 expression, thus identifying C4ST-1 as a negatively regulated target gene of HRAS signaling. Importantly, we show that forced expression of C4ST-1 in Costello fibroblasts could rescue the proliferation and elastogenesis defects associated with oncogenic HRAS signaling in these cells. Our results indicate reduced C4ST-1 expression and chondroitin sulfation imbalance mediating the effects of oncogenic HRAS signaling in the pathogenesis of Costello syndrome. Thus, our work identifies C4ST-1-dependent chondroitin sulfation as a downstream vulnerability in oncogenic RAS signaling, which might be pharmacologically exploited in future treatments of not only Costello syndrome and other RASopathies, but also human cancers associated with activating RAS mutations. [ABSTRACT FROM AUTHOR]

Intoduction: Hydrocephalus has been related to Chiari type I malformation (CIM) for a long time. The pathogenesis of this association is complex and still debated. Discussion: A supratentorial hypertensive hydrocephalus may cause CIM, exerting pressure from above. Another pathogenetic hypothesis is based on the clinical and radiological data from patients affected by complex craniosynostosis, in which this association is more commonly observed as the consequence of a 'cephalo-cranial disproportion' ultimately leading to a secondary hydrocephalus. In some cases, the concomitant presence of a stenosis of the jugular foramina would determine a condition of upward venous hypertension, resulting in the development of CIM and an associated hydrocephalus due to cerebellar parenchyma turgor. Conclusions: The radiological association of ventricular enlargement and hindbrain herniation would be the result of heterogeneous pathogenetic mechanisms which would then require specific therapeutic approaches. In this context, the endoscopic third ventricle-cisternostomy is gaining an increasing interest because of its more physiologic correction of the altered CSF dynamics and its minor interference on the developmental processes responsible for the association of hydrocephalus and CIM. [ABSTRACT FROM AUTHOR]

Noonan syndrome is a highly variable disorder that has significant phenotypic overlap with Costello syndrome and cardio-facio-cutaneous syndrome. KRAS mutation was the second reported gene for Noonan syndrome. This study screened for mutation of the KRAS gene in 57 unrelated ethnic Chinese children suffering from Noonan syndrome without PTPN11 gene mutation in Taiwan. This work only identified two patients with different missense mutations (c.40G>A, p.Val14Ile; c.108A>G, p.Ile36Met) in the exon 1 of KRAS gene. This study also analyzed the characteristics of 34 reported cases involving KRAS mutations in the literature. All these patients presented with variable phenotypes, including Noonan syndrome ( n = 19), cardio-facio-cutaneous syndrome ( n = 7), Costello syndrome ( n = 6), and Noonan/cardio-facio-cutaneous syndrome ( n = 1). The phenotype of KRAS mutations was generally severe, including short stature, mental retardation, heart defects, etc. In conclusion, this investigation demonstrates that KRAS mutations are the cause in a minority of cases of Chinese patients with Noonan syndrome in Taiwan. [ABSTRACT FROM AUTHOR]

We report on three patients with Costello syndrome (CS) diagnosed during the first year of life and try to outline the clinical characteristics facilitating early recognition of this syndrome, which can now be corroborated by testing the HRAS gene. Phenotypical overlap of CS with Noonan (NS) and cardiofaciocutaneous syndrome (CFCS), particularly in neonatal age, is well known. Diagnostic features useful for recognition of CS in the first year of life are the following: (1) fetal and neonatal macrosomia with subsequent slow growth due to severe feeding difficulties, (2) developmental delay, (3) particularly coarse facial dysmorphisms and gingival hyperplasia, (4) skeletal anomalies as osteoporosis and metaphyseal enlargement, (5) hypertrophic cardiomyopathy (HCM) with asymmetric septal thickening and systolic anterior motion of the mitral valve, and (6) specific atrial arrhythmias. Following a clinical suspect of CS based on specific features, molecular screening of HRAS gene mutations should precede analysis of the other genes in the Ras-MAPK pathway implicated in related disorders with overlapping phenotypes. [ABSTRACT FROM AUTHOR]

The RAS-MAPKinase pathway is a signal transduction cascade which has been studied extensively during the last decades for its role in human oncogenesis. Activation of this cascade is controlled by cycling of the RAS protein between an inactive and an active state and by phosphorylation of downstream proteins. The signalling cascade regulates cell proliferation, differentiation and survival. Disturbed RAS signalling in malignancies is caused by acquired somatic mutations in RAS genes or other components of this pathway. Recently, germline mutations in genes coding for different components of the RAS signalling cascade have been recognized as the cause of several phenotypically overlapping disorders, recently referred to as the neuro-cardio-facial-cutaneous syndromes. Neurofibromatosis type 1, Noonan, LEOPARD, Costello and cardiofaciocutaneous syndromes all present with variable degrees of psychomotor delay, congenital heart defects, facial dysmorphism, short stature, skin abnormalities and a predisposition for malignancy. These findings point to important roles for this evolutionary conserved pathway in oncogenesis, development, cognition and growth. Conclusion: it has become obvious in recent years that the neuro-cardio-facial-cutaneous syndromes all share a common genetic and pathophysiologic basis. Dysregulation of the RAS-MAPKinase pathway is caused by germline mutations in genes involved in this pathway. Undoubtedly more genes causing related syndromes will be discovered in the near future since there are still a substantial number of genes in the pathway that are not yet associated with a known syndrome. [ABSTRACT FROM AUTHOR]

Costello syndrome is an autosomal dominant disorder comprising growth deficiency, mental retardation, curly hair, coarse facial features, nasal papillomata, low-set ears with large lobes, cardiac anomalies, redundant skin in palms and soles with prominent creases, dark skin, and propensity to certain solid tumors. HRAS mutations have been implicated in approximately 85% of the affected cases. The clinical overlap among Costello, Noonan, and cardiofaciocutaneous syndromes is now better understood given their common molecular background, such that all these syndromes constitute a class of disorders caused by deregulated RAS-MAPK signaling. We report on a novel KRAS gene mutation in a patient presenting the clinical features typical of Costello syndrome and the additional findings seen in Noonan syndrome. This description emphasizes that a subset of patients with Costello syndrome could harbor mutations in other genes involved in the RAS-MAPK signaling. [ABSTRACT FROM AUTHOR]

The Ras signaling pathway controls important cellular responses to growth factors, and somatic mutations in RAS genes and other components of the Ras pathway, such as PTPN11 (encoding the protein-tyrosine phosphatase SHP-2) and BRAF, are found in human malignancies. Ras proteins are guanosine nucleotide-binding proteins that cycle between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. Neoplasia-associated Ras mutations frequently affect amino acids G12, G13, or Q61 and decrease the intrinsic guanosine triphosphatase (GTPase) activity by ten- to twentyfold. The GTPase activity is crucial for Ras inactivation by hydrolysis and release of a phosphate group from Ras·GTP to produce Ras·GDP. We and others have recently discovered germline mutations in the KRAS gene in individuals diagnosed with Noonan and cardio–facio–cutaneous (CFC) syndrome, two clinically overlapping disorders characterized by short stature, distinct facial anomalies, heart defects, and other abnormalities. Noonan syndrome-associated mutations V14I and T58I K-Ras activate Ras but have milder biochemical effects than somatic mutations encountered in cancers, offering an explanation why these K-Ras lesions are tolerated during embryonic development. Together with recent findings of BRAF, MEK1, and MEK2 mutations in CFC syndrome and HRAS mutations in Costello syndrome, another clinically related disorder, it has now become clear that Noonan-like features (short stature, relative macrocephaly, facial anomalies, learning difficulties) that are found in these three related disorders are a result of constitutive activation of the Ras–Raf–extracellular signal-regulated and mitogen-activated protein kinase pathway. [ABSTRACT FROM AUTHOR]

A 5-year-old girl with the Costello syndrome is reported. Her clinical manifestations included growth and developmental delay, a distinct facial appearance with sparse and curly hair, nasal papillomata, and dark loose skin of the hands and feet. These manifestations, especially nasal papilloma, an age-dependent anomaly, are distinct in the Costello syndrome. [ABSTRACT FROM AUTHOR]

Two patients with the Costello syndrome are presented. One was a 7-year-old girl with a history of infantile hypotonia and feeding difficulties. The other was a 3 5/12-year-old boy with a history of neonatal sepsis and respiratory problems. Both had relative macrocephaly at birth, curly hair, large ear lobes, epicanthic folds, a low nasal bridge, thick lips, a short and wide nose, a short neck, a barrel chest, redundant skin, tight Achilles tendons, and pes equinovarus. Nasal papillomata, as described in Costello's two patients, were absent in both patients. Borochowitz et al. (1992) described five patients with what we interpreted as the Costello syndrome but without nasal papillomata. In view of these findings, nasal papillomata are not likely to be essential in the diagnosis of the Costello syndrome. [ABSTRACT FROM AUTHOR]

A 3-year-old boy with Costello syndrome is reported. He had typical clinical features of the syndrome including severe postnatal growth retardation, poor sucking, mild developmental delay, a coarse characteristic facies, thick and loose skin of the hands and feet, sparse and curly hair, dark skin, and relative macrocephaly but lacked nasal papillomas. In addition, he had cardiac anomalies with extrasystoles and thick mitral valve tips. Mitral valve defects may be a clinical feature of the syndrome. [ABSTRACT FROM AUTHOR]

Bladder tumours of patients <20 years have a low incidence of genetic aberrations typically found in tumours in older patients. In this study, we investigated oncogene mutations in patients with bladder cancer (BC) <20 years and compared them to older age groups. Interestingly, we observed a relatively high number of HRAS mutations in tumour from young patients. These mutations were also highly uncommon in BCs of older patients, ie, p.(Gly12Ser) and p.(Gly12Ala). Germline mutations in the HRAS gene, especially p.(Gly12Ser/Ala), cause Costello Syndrome (CS), a severe congenital disorder. Indeed, one of the patients had been diagnosed with CS. We hypothesized that some of the other patients might be mosaic for the HRAS mutation and therefore could express some of the clinical features of CS, like tumour predisposition. Hence, we isolated DNA from microdissected stroma and analysed it for HRAS mutations. In the CS patient and in patient X, the mutation was also highly expressed in normal stroma. We conclude that patient X is possibly mosaic for the HRAS mutation. These results suggest that mosaicism for oncogenic HRAS mutations may increase the risk for developing BC at a young age. [ABSTRACT FROM AUTHOR]