Further delineation of cardiac abnormalities in Costello syndrome

Abstract

We review the cardiac abnormalities in 94 patients (27 new, 67 literature) with Costello syndrome, an increasingly recognized syndrome consisting of increased birth weight, postnatal growth retardation, and distinctive facial, skin, and musculoskeletal features (MIM 218040). A cardiac abnormality was found in 59 (63%) patients, with each of three categories occurring in approximately one-third of patients. A cardiovascular malformation (CVM) was noted in 30%, typically pulmonic stenosis (46% of those with a CVM). Cardiac hypertrophy was reported in 34%, which involved the left ventricle in 50% and was usually consistent with classic hypertrophic cardiomyopathy (HCM). A variety of rhythm disturbances were reported in 33%. Most (74%) were atrial tachycardia that was reported as supraventricular, chaotic, multifocal, or ectopic. Of 31 patients with a rhythm abnormality, 22 (68%) had an additional abnormality, i.e., CVM (4), cardiac hypertrophy (12), or both (6). Nine patients had isolated dysrhythmia, five (56%) of whom died. All of the 12 (13%) patients who died had a cardiac abnormality. One patient died of embryonal rhabdomyosarcoma, but in the remainder, a cardiac cause of death could not be disproved. All patients with Costello syndrome need a baseline cardiology evaluation with echocardiography and Holter monitoring. Additional prospective evaluations, even in patients without apparent cardiac abnormalities, would be prudent, although data are insufficient to propose a specific schedule.

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

“…There is less detailed information about patient age in Lin et al [2002] with a general mean age calculated as 4.6 years, not directly comparable to the mean age at diagnosis (4.2) or current age (12) in this study. There has been no report of fetal HCM, which may reflect ascertainment, given the multiple reports of neonatal HCM [Hinek et al, 2005;Digilio et al, 2007;Limongelli et al, 2008;Lo et al, 2008].…”

“…These occurred in a 5 1 = 2 -year-old boy with the common p.G12S mutation and HCM, thickened aortic and mitral valves and marked myocardial fiber disarray [Supplemental Appendix patient 5, Lin et al, 2002;patient 3 in Hinek et al, 2005], and a 27-year-old male with severe HCM, non-sustained atrial and ventricular ectopy and mild ascending aortic dilation (Table III). Postmortem examination confirmed severe HCM (360 g), and showed myxomatous mitral and tricuspid valves, a fenestrated thick aortic valve, mildly dilated ascending aorta (normal Sinus of Valsalva), and a plaque of anterior systolic motion of the mitral valve (Supplemental Appendix patient 2, Fig.…”

Costello syndrome with growth hormone deficiency and hypoglycemia: A new report and review of the endocrine associations

“…This hypothesis is supported by the reports of combined GH and cortisol deficiency in the patient of Yetkin et al [1998] (and strongly suspected in our patient), combined GH and thyroid hormone deficiency in the patient of Gripp et al [2000], the other reported cases of isolated GH deficiency [Okamoto et al, 1994;Schimke et al, 1996;Legault and Gagnon, 2002;Delrue et al, 2003]], and mention of elevated prolactin levels in one patient with CS [Johnson et al, 1998]. Lin et al [2002] speculated that GH therapy in CS patients may cause the progression of existing cardiac hypertrophy, or initiate hypertrophy in patients with an apparently normal myocardium. Further, they expressed concern about the safety of GH replacement therapy in a syndrome with a known predisposition to neoplasia.…”

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

“…30,42 Rather than propose a unique set of guidelines, we advise providers and families to receive individualized care by However, the medical issues seen in Costello syndrome may resemble those seen in other rasopathies, for example, the HCM in Noonan syndrome and CFC syndrome, the skin findings shared with CFC syndrome, or the low bone density and increased tumor risk in NF1. In fact, the phenotype of Costello, Noonan, and CFC syndromes shows such significant overlap during infancy that a clear distinction cannot always be made on clinical criteria alone, but rather molecular testing is necessary.…”

“…Based on a recent analysis of 61 study and 85 previously reported patients with HRAS mutation analysis, 87% of individuals with Costello syndrome have some type of a cardiovascular abnormality, increased from a prior report based on clinically diagnosed patients (60%). 30 A congenital heart defect was present in 44%, usually nonprogressive valvar pulmonic stenosis, rarely associated with certain rare mutations, including p.Gly12Asp and p.Gly12Cys. In contrast, the possibility of a milder or attenuated phenotype was noted in individuals with p.Thr58Ile and p.Ala146Val.…”