Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.
hemolytic uremic syndrome, and Clarkson disease in adults. 1,3,4 We propose that Ang-2 plays a critical role even in children with Clarkson disease. Genetic factors might also be involved in the pathogenesis because a case with Clarkson disease due to a mutation of ARHGAP5 encoding p190Rho-GAP was recently reported. 5 In conclusion, the challenging diagnosis of Clarkson disease deserves consideration in previously healthy children with acute onset of anasarca associated with the "three Hs" triad of hypoperfusion, hemoconcentration, and hypoproteinemia. Measurement of serum Ang-1 and Ang-2 levels might be helpful for diagnosing this condition. Declaration of patient consent The authors certify that they have obtained written consent from the patient's guardians. They understand that the patient's name and initials will not be published and due effort will be made to conceal his identity.
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