Proceedings from the 2009 genetic syndromes of the Ras/MAPK pathway: From bedside to bench and back

Abstract

The RASopathies are a group of genetic syndromes caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Some of these syndromes are neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, LEOPARD syndrome and Legius syndrome. Their common underlying pathogenetic mechanism brings about significant overlap in phenotypic features and includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium “Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back” chronicle the timely and typical research symposium which brought together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras syndromes and their families. The goals, to discuss basic science and clinical issues, to set forth a solid framework for future research, to direct translational applications towards therapy and to set forth best practices for individuals with RASopathies was successfully meet with a commitment to begin to move towards clinical trials.

Assessing genotype–phenotype correlation in Costello syndrome using a severity score

“…15 Although the severity scoring system described here cannot measure the short-term effects of drug treatment, it is useful in quantifying the differences in severity anticipated with the respective mutations and may thereby guide enrollment criteria. Furthermore, changes in the long-term outcome may be assessed through this severity score.…”

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

“…In light of the many similar medical issues for individuals with any rasopathy, a clinic model combining patients with these conditions is beneficial as it allows the specialists to become more familiar with these conditions. 50 Two of the rasopathies, NF1 and Noonan syndrome, are relatively common, and most healthcare institutions are familiar with their phenotype and medical issues. Specialists, such as cardiologist caring for Noonan syndrome individuals, can become familiar with the phenotypic presentation and may be more comfortable caring for a patient with Costello syndrome.…”

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

“…Costello syndrome (MIM #218040) is a rare multiple anomaly syndrome , and beyond infancy, can be differentiated from phenotypically similar Ras/MAPK pathway syndromes (''RASopathies'') [Rauen et al, 2010], that is, Cardiofaciocutaneous (CFC) syndrome (#115150) and Noonan syndrome (#163950). Other RASopathies which have similar pathogenetic activation of Ras/MAPK, but have little phenotypic overlap include Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome) (#151100, #611554), capillary malformationarteriovenous malformation syndrome (#139150), or neurofibromatosis type 1 (#162200) [Quezada and Gripp, 2007;Denayer et al, 2008;Tidyman and Rauen, 2008;Rauen et al, 2010].…”

“…Other RASopathies which have similar pathogenetic activation of Ras/MAPK, but have little phenotypic overlap include Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome) (#151100, #611554), capillary malformationarteriovenous malformation syndrome (#139150), or neurofibromatosis type 1 (#162200) [Quezada and Gripp, 2007;Denayer et al, 2008;Tidyman and Rauen, 2008;Rauen et al, 2010]. Phenotypic features of Costello syndrome include polyhydramnios, increased birth weight, feeding problems, failure to thrive, short stature, developmental delay, pleasant personality, characteristic facial appearance, soft skin, papillomata, spatulate fingerpads, deep palmar creases, joint and skin laxity, kyphoscoliosis, pectus, and splayed fingers with ulnar deviation.…”