Costello syndrome is a rare genetic disorder, initially described in 1971,Reference Rauen, Hefner and Carrillo1 caused by activating germline mutations in RAS proto-oncogenes, and characterized by prenatally increased growth, postnatal growth retardation, coarse facies, loose skin resembling cutis laxa, developmental delay, cardiac abnormalities, and an outgoing, friendly behaviour.Reference Costello2 Cardiac abnormalities are found in up to three-quarters of the patients,Reference Johnson, Golabi and Norton3, Reference Siwik, Zahka, Wiesner and Limwongse4 and can be summarised in terms of cardiovascular malformations, cardiac hypertrophy, and disturbances of rhythm, each occurring in approximately one-third of patients with cardiac involvement.Reference Lin, Grossfeld and Hamilton5 Contrary to the clinical cardiac phenotype, the management of these cardiac abnormalities is very poorly documented, according to the first International Costello Syndrome Research Symposium,Reference Rauen, Hefner and Carrillo1 must represent one of the major research directions. Our objective in this report, therefore, is to describe 2 new children with Costello syndrome complicated with obstructive cardiac hypertrophy requiring surgery, comparing their cardiac anatomical characteristics as revealed by ultrasound to those previously described, and based on these findings, to propose a combined medical and surgical approach to treatment.
Case Reports
We summarise the gender, age, and cardiac abnormalities of our patients in Table 1. The features of their medical and surgical management is summarised in Table 2.
Table 1 Demographic and cardiac abnormalities in our patients.
Table 2 Characteristics of the medical and surgical management.
Discussion
We report here our experience with 2 children diagnosed with Costello syndrome complicated with diffuse and asymmetric hypertrophic obstructive cardiomyopathy. The asymmetric component of the septal htpertrophy was successfully treated with surgical myomectomy, while we treated the diffuse non-obstructive component using beta-blockers.
The absence of involvement of siblings in either case supports the proposal that Costello syndrome is caused by sporadic mutations.Reference Lurie6 The extracardiac findings in our children are consistent with those noted in the first reported cases, and with those emphasised by subsequent reviews.Reference Rauen, Hefner and Carrillo1–Reference Johnson, Golabi and Norton3 As for the cardiac abnormalities, previous reports show that the combination of cardiac hypertrophy, atrial tachycardia, and mild pulmonary stenosis is characterisric, but not pathognomonic, for the syndrome.Reference Rauen, Hefner and Carrillo1 An extensive review of the literature showed that a cardiovascular malformation is present in almost one-third of patients with the syndrome, with almost half of these patients having pulmonary stenosis.Reference Lin, Grossfeld and Hamilton5 Neither of our patients, however, had pulmonary stenosis. This is consistent with recent genetic studies showing that the cardiovascular malformations, especially pulmonary stenosis associated with an interatrial communication across the oval fossa, are significantly more common in the cardio-facial-cutaneous syndrome with BRAF or MEK1 mutations than in Costello syndrome.Reference Rauen, Hefner and Carrillo1, Reference Gripp, Lin and Nicholson7 Abnormal leaflets of the mitral valve had been described as myxomatous, redundant, or thick in 6 patients with Costello syndrome,Reference Izumikawa, Naritomi, Tohma, Shiroma and Hirayama8 whereas our first patient had abnormally tendinous cords supporting normal mitral valvar leaflets. The presence of a supraventricular tachycardia in our second patient is also consistent with previous experience, this being the disturbance of rhythm noted in three-quarters of patients with the syndrome. The tachycardia noted in our patient, however, is probably not only due to the syndrome, but rather to perioperative stress. There are 2 reasons supporting this presumption: first the abnormal rhythm was neither chaotic, multi-focal nor ectopic, as would be expected for Costello syndrome, and second, it did not become manifest until after surgical relief of the cardiac hypertrophy, a happening which, to the best of our knowledge, is thus far unique.
When we compare the characteristics of cardiac hypertrophy in our patients with other reported experience, we find that this purportedly classical feature of Costello syndrome is very heterogeneous in terms of its anatomical distribution, onset, natural history, and prognosis.
When considering the anatomical distribution, asymmetric septal thickening along with anterior systolic motion of the aortic leaflet of the mitral valve is most characteristic.Reference Lin, Grossfeld and Hamilton5 Both of our patients, however, presented more complex patterns of hypertrophy, which at the same time was diffuse and non-obstructive, involving both ventricles, and asymmetric and obstructive, involving the subaortic left ventricular outflow tract.
With regard to onset, the hypertrophy is said to appear between the ages of 5 months and 20 years.Reference Siwik, Zahka, Wiesner and Limwongse4 Follow-up of the original patients described by Costello,Reference Costello2 nonetheless, showed hypertrophy becoming evident at the age of 27 years. The early occurence of cardiac hypertrophy in our second patient confirms that hypertrophy can also be found in neonates with the syndrome.Reference Lin, Grossfeld and Hamilton5
When considering natural history, then contrary to the data presented in the extensive review,Reference Lin, Grossfeld and Hamilton5 the evolution of myocardial hypertrophy in both our patients was not in keeping with its phenotypic progression.Reference Lin, Grossfeld and Hamilton5
Prognosis can be sometimes excellent, as in both our patients, but is sometimes fatal.Reference Costello9, Reference Tomita, Fuse, Ikeda, Matsuda and Chiba10 On the basis of this complex anatomical, evolutive, and prognostic heterogeneity, we believe that the medical and surgical teams should treat patients with the syndrome on an individual basis.
In this respect, it was the diffuse and asymmetric hypertrophic cardiomyopathy encountered in our patients that accounted for the decreased left ventricular compliance, subaortic stenosis, and mitral regurgitation. Only the latter 2 elements were accessible to surgical septal myomectomy. Such myomectomy did not improve the diffuse hypertrophy that persisted in both patients, but it prevented any recurrence of subaortic stenosis as judged at mid-term follow-up. Thus, we suggest that the heterogeneous cardiac hypertrophy encountered in Costello syndrome should be managed, on the one hand, as a diffuse feature accessible to a medical treatment by beta-blockade, but on the other hand as asymmetric hypertrophy accessible to surgery.
