We are grateful for the insightful response by Dr Calcagni and colleagues to our case report1 on the presence of mitral valve abnormalities in an adult patient to whom we gave a diagnosis of Costello syndrome. We are pleased to see that our findings resonate with their considerable experience in the broader context of RASopathy syndromes among the pediatric population.
We fully agree with their observation that mitral valve (MV) disease, particularly in the context of RASopathies, serves as an important marker of clinical complexity. Their focus on the anatomical characteristics of MV disease, including the abnormal and dysplastic anterior leaflet insertion, as constituting a critical feature for early diagnosis is compelling. These valvular anomalies can indeed be pivotal for identifying Costello syndrome during the early stages of life.
Our case of Costello syndrome was unusual with respect to the age at presentation. Most patients received the diagnosis in infancy,2 but it was not until our patient was referred following syncope as an adult to a dedicated inherited cardiovascular conditions unit that the diagnosis was made after genetic panel testing for RASopathies. A high proportion of cases are diagnosed in infancy after the detection of hypotonia leading to poor neonatal feeding, as well as the subsequent identification of developmental delay and nasal papillomata. Our patient’s hypotonia and failure to thrive were identified in infancy but had initially been attributed to fetal alcohol syndrome following a history of alcohol dependence in his estranged mother.
It is notable that the CARNET study highlighted a high prevalence (80.3%) of cardiac defects, including MV abnormalities among pediatric cases of Costello syndrome,3 but no studies to date have reported these specific data in the adult population. This case underscores the importance of maintaining vigilance and suggests that the detection of MV defects is likely to play a critical role in the identification of Costello syndrome across all age groups.
In conclusion, we agree that MV disorders should not be considered “minor” defects in RASopathies. When we assess the entire cardiac spectrum, a particular focus on the valvular phenotype is crucial if we are to achieve a timely diagnosis and treatment of this rare genetic condition.
Footnotes
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
- 1.Naneishvili T., Yuan M., Mansour M., Moody W.E., Steeds R.P. Dysplastic mitral valve in Costello syndrome. JACC Case Rep. 2024;29(14) doi: 10.1016/j.jaccas.2024.102408. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Digilio M.C., Sarkozy A., Capolino R., et al. Costello syndrome: clinical diagnosis in the first year of life. Eur J Pediatr. 2008;167:621–628. doi: 10.1007/s00431-007-0558-0. [DOI] [PubMed] [Google Scholar]
- 3.Calcagni G., Limongelli G., D'Ambrosio A., et al. Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results. Int J Cardiol. 2017;245:92–98. doi: 10.1016/j.ijcard.2017.07.068. [DOI] [PubMed] [Google Scholar]