Prenatal features of Costello syndrome: ultrasonographic findings and atrial tachycardia

Abstract

Objective Delineate prenatal features of Costello syndrome (caused by HRAS mutations) which consists of mental retardation, facial, cardiovascular, skin, and musculoskeletal anomalies, and tumor predisposition. Methods Literature and new cases classified as Group I (pre-HRAS), Group II (HRAS confirmed), and Group III (HRAS confirmed in natural history study, plus three contributed cases). Results Polyhydramnios occurred in most (mean 79%) pregnancies of cases in Groups I (98), II (107), and III (17), advanced paternal age and prematurity were noted in approximately half. Less frequent were nuchal thickening, ascites, shortened long bones, abnormal hand posture, ventriculomegaly, macrosomia, and macrocephaly. Fetal arrhythmia occurred in 9 cases (6 supraventricular or unspecified tachycardia, 1 unspecified arrhythmia, 2 premature atrial contractions, PACs); excluding 3 new cases and 2 with PACs, the estimated prenatal frequency is 4/222 (2%). Conclusion Costello syndrome can be suspected prenatally when polyhydramnios is accompanied by nuchal thickening, hydrops, shortened long bones, abnormal hand posture, ventriculomegaly, large size, and macrocephaly, and especially fetal atrial tachycardia. Consideration should be given for timely prenatal diagnostic studies for confirmative HRAS gene mutations, and for maternal treatment of serious fetal arrhythmia.

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

“…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.…”

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

“…Prenatally, increased nuchal thickness, polyhydramnios (>90%), characteristic ulnar deviation of the wrists, and short humeri, and femurs can be seen on ultrasonography. 26,27 Because most features of the fetal phenotype are not unique (such as ventriculomegaly and macrocephaly), and as Costello syndrome is rare, the diagnosis is often not considered prenatally. Cardiac hypertrophy has not been reported, but fetal atrial tachycardia has been detected in at least five fetuses subsequently diagnosed with Costello syndrome, and it increases the index of suspicion for this diagnosis.…”

“…Cardiac hypertrophy has not been reported, but fetal atrial tachycardia has been detected in at least five fetuses subsequently diagnosed with Costello syndrome, and it increases the index of suspicion for this diagnosis. 26 Increased birth weight and head circumference (often >50th percentile) for gestational age can lead to the misclassification of Costello syndrome as "macrosomia. " Hypoglycemia is common in neonates.…”

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

“…The number of fatal cases was 5/138 patients with p.G12S, 4/6 with p.G12C, 3/17 with p.G12A, 3/4 with p.G12D, 2/2 with p.G12V, 1/1 with p.G12E and 1/1 with p.E63K. 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The mortality of patients with p.G12C or p.G12D was significantly higher than that of the patients with the more common p.G12S (P¼0.026 by Fisher's exact test). Previous studies have shown that the p.G12V substitution has the highest transformative potential (p.G12V4p.G12A, p.G12S, p.G12C, p.G12D4p.G13D) and is the most frequently found mutation in human tumors.…”

“…3 It has been suggested that the CS diagnosis should be applied only to patients with a mutation in HRAS because of the high risk of malignancies associated with HRAS mutations and the relative homogeneity of the CS phenotype. 4 A total of 14 HRAS missense mutations and one duplication mutation have been reported in 185 patients with CS 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] or congenital myopathy with excess of muscle spindles. 24 Most of these mutations have previously been reported as somatic and oncogenic mutations in various tumors.…”