Prenatal findings of hypertrophic cardiomyopathy in a severe case of Costello syndrome.

Abstract

Costello syndrome (CS) is a genetic disorder resulting from mutations in the HRAS gene and is characterized by a distinctive facial appearance, loose folds of skin, developmental delay, cardiac abnormalities and a predisposition to tumor development1-3. A major contributory factor to neonatal prognosis is the association with cardiac abnormalities including arrhythmia, congenital defects and hypertrophic cardiomyopathy (HCM). Here we report on the prenatal findings of HCM in a severe case of CS. A 26-year-old primigravida was referred for detailed ultrasound assessment at 12 weeks of gestation, which showed increased nuchal translucency thickness, small nasal bones, micrognathia, low-set ears, tricuspid valve regurgitation and reversed flow in the ductus venosus (DV). Chromosomal analysis following chorionic villus sampling revealed a normal 46,XX fetal karyotype. Repeat ultrasound at 22 weeks of gestation revealed fetal overgrowth (>2.5 SD compared to local standards), polyhydramnios, micrognathia and low-set ears (Figure 1a). The findings were suggestive of CS and further genetic analysis was offered, however the parents declined investigation until after birth. Due to a shortened uterine cervix, the mother was hospitalized at 25 weeks of gestation. New fetal findings were observed including highly echogenic thickened subcutaneous tissue in the thorax (Figure 1b), hypertrophic cardiomyopathy and a septum in the left atrium that was revealed postnatally to be cor triatriatum (Figure 1c). Doppler ultrasonography revealed fused E- and A-waves in bilateral ventricular filling patterns with very high speed (Figure 1d,e) as well as fused S- and D-waves of DV flow velocity waveforms (Figure 1f). Although we performed amniodrainage twice, uterine contractions increased and a 2112-g female was delivered vaginally at 31 + 4 weeks of gestation. The neonate had a coarse face, high forehead, broad nasal tip, thick lips and low-set ears, suggestive of CS. Neonatal echocardiography confirmed hypertrophic cardiomyopathy and cor triatriatum. Transient tachycardia, ranging from 180 to 250 bpm, was observed at 3 days old and became sustained at > 200 bpm from 7 days old and pharmacotherapy was initiated. The infant died at 35 days old due to ectopic (chaotic) atrial tachycardia. CS was confirmed by genetic testing, which identified a missense mutation (c.35 T > C, p.G12D) in the HRAS gene. Arrhythmia is a relatively frequent cardiac condition diagnosed during the perinatal period in CS, whereas HCM tends to be recognized at a relatively later stage1, 3. The present case showed apparent HCM at 25 weeks' gestation along with a highly abnormal blood-flow pattern in the ventricles and DV. Impaired diastolic function may shorten the duration of atrioventricular valve opening, leading to fusion of the E- and A-waves. This phenomenon results in a shortened time interval for the D-wave or fused S- and D-waves in the DV, as cardiac phases are reflected in the time interval for DV blood-flow patterns4, 5. The strikingly increased velocity of ventricular blood inflow might also be explained by the impaired diastolic function, which may lead to larger atrial blood volume and subsequent increases to inflow on atrial contraction. We report the finding of prenatal HCM in a severe case of CS. The genetic mutation in this case of CS seemed to be relatively rare, and the patient was severely affected. Our findings provide additional information on the perinatal outcome of cases with this mutation that should aid in genetic counseling. Doppler echocardiography may provide useful information for understanding fetal cardiac function and associated pathophysiology in CS. We thank the physicians who contributed to the diagnosis and management of this case: Kenji Fujita, Yoh Kawauchi, Mika Saito, Department of Pediatrics, Osaka City University Graduate School of Medicine; Tsugutoshi Suzuki, Yosuke Murakami, Department of Pediatric Cardiology and Electrophysiology, Osaka City General Hospital; Masako Yaoita, Department of Medical Genetics, Tohoku University School of Medicine. R. Uemura*†, D. Tachibana†, Y. Kurihara†, R. K. Pooh‡, Y. Aoki§ and M. Koyama† †Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka, Japan; ‡CRIFM Clinical Research Institute of Fetal Medicine PMC, Osaka, Japan; §Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan *Correspondence. (e-mail: [email protected])