Costello syndrome: clinical diagnosis in the first year of life

Abstract

We report on three patients with Costello syndrome (CS) diagnosed during the first year of life and try to outline the clinical characteristics facilitating early recognition of this syndrome, which can now be corroborated by testing the HRAS gene. Phenotypical overlap of CS with Noonan (NS) and cardiofaciocutaneous syndrome (CFCS), particularly in neonatal age, is well known. Diagnostic features useful for recognition of CS in the first year of life are the following: (1) fetal and neonatal macrosomia with subsequent slow growth due to severe feeding difficulties, (2) developmental delay, (3) particularly coarse facial dysmorphisms and gingival hyperplasia, (4) skeletal anomalies as osteoporosis and metaphyseal enlargement, (5) hypertrophic cardiomyopathy (HCM) with asymmetric septal thickening and systolic anterior motion of the mitral valve, and (6) specific atrial arrhythmias. Following a clinical suspect of CS based on specific features, molecular screening of HRAS gene mutations should precede analysis of the other genes in the Ras-MAPK pathway implicated in related disorders with overlapping phenotypes.

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]. We now include mild interventricular septal ''thickening'' as HCM since previously unclassified cases have now been observed to progress to typical HCM.…”

“…The literature tends to be biased towards the severe forms of Costello syndrome, such as the fetal phenotype [Kuniba et al, 2009;Lin et al, 2009;Smith et al, 2009] and lethal infantile presentation [Hinek et al, 2005;Digilio et al, 2007;Limongelli et al, 2008;Lo et al, 2008], thus, our study patients expand the phenotypic spectrum to the mild end. It is reasonable to assume that diagnosis of Costello syndrome is more likely to be missed in early lethal cases when infants with hypertrophic cardiomyopathy and hypotonia may be diagnosed as having a metabolic or mitochondrial disease.…”

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome

“…Curly and/or sparse hair (21/21), failure to thrive (21/21), coarse facial appearance (20/20), deep palmar/planter creases (20/21), soft, loose skin (18/21) and relative macrocephaly (17/21) were observed at high frequency in patients with CS, as previously reported. 1,3 Laryngomalacia (soft larynx), which has been reported in several patients with CS, [36][37][38] was observed in three patients. One patient had hypertension, which was also observed in a mouse model of CS.…”

Eponyms related to genetic disorders associated with gingival enlargement; part I

“…Costello syndrome (CS) [5,6] It is a distinctive rare multisystem disorder comprising a characteristic coarse facial appearance, intellectual disabilities, and tumor and papillomata predisposition. Heart abnormalities are also common.…”