How to Cite this Article: Burkitt-Wright EMM, Bradley L, Shorto J, McConnell VPM, Gannon C, Firth HV, Park S-M, D'Amore A, Munyard PF, Turnpenny PD, Charlton A, Wilson M, Kerr B. 2012. Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val. Am J Med Genet Part A. 158A:1102–1110.
Article first published online: 11 APR 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 158A, Issue 5, pages 1102–1110, May 2012
How to Cite
Burkitt-Wright, E. M.M., Bradley, L., Shorto, J., McConnell, V. P.M., Gannon, C., Firth, H. V., Park, S.-M., D'Amore, A., Munyard, P. F., Turnpenny, P. D., Charlton, A., Wilson, M. and Kerr, B. (2012), Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val. Am. J. Med. Genet., 158A: 1102–1110. doi: 10.1002/ajmg.a.35296
Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms
The authors have no competing interests to declare.
- Issue published online: 18 APR 2012
- Article first published online: 11 APR 2012
- Manuscript Accepted: 29 DEC 2011
- Manuscript Received: 18 OCT 2011
- Wellcome trust
- UK National Institute for Health Research's Manchester Biomedical Research Centre
- Costello syndrome;
- neonatal cardiomyopathy;
- congenital alveolar dysplasia;
- dinucleotide insertion/deletion mutation
De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition. © 2012 Wiley Periodicals, Inc.