Cardiac-Urogenital Syndrome

A number sign (#) is used with this entry because of evidence that cardiac-urogenital syndrome (CUGS) is caused by heterozygous mutation in the MYRF gene (608329) on chromosome 11q12.

Description

Cardiac-urogenital syndrome is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism (Pinz et al., 2018).

Clinical Features

Pinz et al. (2018) reported 2 unrelated male infants with partial anomalous pulmonary venous return in association with urogenital anomalies. The first was a 3-year-old boy who had mesocardia noted on prenatal ultrasound, in whom postnatal echocardiogram and cardiac MRI showed severely obstructive left atrial cor triatriatum as well as connection of the right middle and upper pulmonary veins to the inferior vena cava just below the diaphragm, via an additional scimitar vein. Bronchoscopy and CT imaging revealed right pulmonary hypoplasia, distal tracheal narrowing, atypical right bronchus with early branching to right upper and middle lobes, and severe right middle lobe bronchomalacia with narrowing and external compression. He also had hypospadias with micropenis and unilateral cryptorchidism. The second patient was a male infant in whom postnatal echocardiogram showed near-interruption of the aortic arch with transverse arch hypoplasia and hypoplastic mitral valve, large ventricular septal defect, large patent ductus arteriosus, dextroposition and hypoplasia of the right pulmonary artery, and mild dilation with hypertrophy of the right ventricle. He also had narrowing of the mid and distal thoracic trachea, as well as right congenital diaphragmatic hernia (CDH), with extension of the hepatic dome into the right hemithorax. At repair of the diaphragmatic hernia, intestinal malrotation was discovered and repaired. Postoperatively he became anuric and died at day 10 of life. Additional findings at autopsy included persistent left vena cava draining into a dilated coronary sinus, and partial anomalous pulmonary venous return involving normally placed left pulmonary veins draining to the left atrium with 2 right pulmonary veins draining into the inferior vena cava. The diaphragmatic hernia had resulted in pulmonary-hepatic fusion with right pulmonary hypoplasia, the thyroid showed interstitial fibrosis, and the thymus was involuted. Persistent urachus was present, and both testes were in the inguinal canal.

Chitayat et al. (2018) described a male fetus of Ashkenazi Jewish descent in whom ultrasound at 19 weeks' gestation showed hypoplastic left heart and female external genitalia. The pregnancy was terminated, and autopsy showed ambiguous external genitalia with small phallic structure, poorly defined urethral meatus, bifid scrotum, and no vaginal opening. There was right hepatotesticular fusion and left splenotesticular fusion. Cardiac findings included hypoplastic left heart sequence with rudimentary left ventricle, aortic and mitral valve atresia, severe hypoplasia of the left atrium, tubular hypoplasia of the ascending aorta, total anomalous pulmonary venous connection to the right atrium, tricuspid valve dysplasia, and retroesophageal right subclavian artery. In addition, there was mild pulmonary hypoplasia, malrotation of the small intestine, and a Meckel band. The authors noted that the phenotype in this fetus was very similar to that of the male infants previously reported by Pinz et al. (2018).

Qi et al. (2018) reported 3 female and 4 male patients from 6 families with congenital heart and urogenital defects. Cardiac defects included atrial and ventricular septal defects, hypoplastic left heart, dextrocardia, tetralogy of Fallot, and scimitar syndrome. Urogenital anomalies included ambiguous genitalia, undescended testes, 46,XY complete gonadal dysgenesis (Swyer syndrome with female genitalia), and blind-ending vagina with absence of internal genital organs in an XX patient. Five of the 7 patients had congenital diaphragmatic hernia. Other malformations included right pulmonary hypoplasia and accessory spleen in 1 patient each, and 1 patient displayed intellectual disability and motor delay. Noting that a monozygotic female twin pair was discordant for CDH, the authors suggested that the manifestation of CDH in this syndrome depends on other genetic, environmental, or stochastic factors.

Molecular Genetics

In 2 unrelated male infants with cardiac-urogenital syndrome, Pinz et al. (2018) identified heterozygosity for de novo mutations in the MYRF gene, a splice site variant (608329.0002) and a nonsense mutation (R840X; 608329.0003), respectively, that were not found in the gnomAD database.

In a male fetus with complex congenital heart disease and severe urogenital malformations, Chitayat et al. (2018) identified heterozygosity for a de novo frameshift variant in the MYRF gene (608329.0004).

Qi et al. (2018) examined whole-exome or whole-genome sequencing data from 271 parent-child trios from a CDH cohort and identified 7 patients from 6 families with heterozygous mutations in the MYRF gene (see, e.g., 608329.0005 and 608329.0006). All of the patients had cardiac defects, and urogenital defects were present in all 4 patients who were examined.