Congenital diaphragmatic hernia and double-outlet right ventricle: elements of trisomy 18?

Introduction

It is well known that congenital diaphragmatic hernia (CDH) is associated with chromosomal anomalies, such as trisomies 13 and 18. At least one fourth of the patients with CDH also have cardiovascular malformations (CVMs). The most common malformations are ventricular septal defects and atrial septal defects. The less commonly documented are Fallot’s tetralogy, hypoplastic left heart syndrome and dextrocardia, transposition of great vessels, double-outlet right ventricle (DORV) and aortic coarctation. Graziano [1] reported that 10.6% of patients with CDH had significant CVMs, out of which 3.2% had DORV.

On the other hand, DORV is a relatively rare diagnosis in the common autosomal trisomies. Nonetheless, the common trisomies 18 and 13 comprise a substantial fraction of the reported chromosomal associations with DORV. One necropsy study examining CVMs associated with chromosomal abnormalities reported a DORV prevalence of 12%, but no cases of DORV associated with trisomy 21 [2].

The association of CDH and DORV in this patient with trisomy 18 might have occurred by chance. In this report, after obtaining the written consent from the parents, we present a case of CDH and DORV. We performed an antenatal diagnosis to confirm the association with trisomy 18. To the best of our knowledge, currently there are limited references in the literature about the co-occurrence of CDH, DORV and trisomy 18 [3].

Case presentation

A term male neonate was born with a vague prenatal history of diaphragmatic hernia and DORV. Maternal history included four miscarriages and six unsuccessful in vitro fertilization (IVF) attempts and the current pregnancy was the result of natural conception. The mother was 35 years old and the father was 43 years old. Both the parents underwent genetic testing due to their history. The karyotype revealed normal 46XX genotype for the mother and 46XY genotype for the father with a pericentric inversion (9p11q13).

The first ultrasound screening test at the gestational age of 12 + 2 weeks revealed the following: crown rump length (CRL) 52.0 mm, nuchal translucency (NT) 6.90 mm and normal tricuspid Doppler. Pregnancy-associated plasma protein A (PAPP-A) and β-human chorionic gonadotropin (β-HCG) levels were not performed. From these findings, the modified risk for trisomies 21, 18 and 13 was estimated as 1/10, 1/5 and 1/88, respectively, as it was calculated using the algorithm FMF – 2012 (v. 3.0) [4]. The parents refused to proceed to chorionic villus sampling (CVS) due to their religious beliefs.

The second ultrasound test of major anatomy of the fetus was scheduled at the gestational age of 20 + 2 weeks. Ventriculomegaly, CDH, displacement of the heart to the right hemithorax, bilateral club feet and bilateral clinodactyly of the upper limbs were detected. It was characterized as a “picture of genetic syndrome”. The parents again refused to proceed to amnioparacentesis for the same reasons.

The last ultrasound test at the gestational age of 38 + 2 weeks, when the parents visited the obstetrician, showed intrauterine growth restriction with pathological pulsatile index (PI) of the umbilical artery in the Doppler and minimal movements of the fetus. At that time point, a perinatal consultation was arranged. It was proposed to proceed to an ultrasound (U/S) fetal heart evaluation and a new detailed U/S anatomy report. The fetal heart echocardiography revealed DORV heart defect with hypoplastic left cavities, coarctation of the aorta, sizable ventricular septal defect and relatively thick semilunar and atrioventricular valves. It was decided to perform an in utero transfer to our hospital, which is a tertiary center.

A male neonate was born by a lower segment cesarean section at the gestational age of 39 weeks. The birth weight was 1840 g corresponding to <3^rd percentile in growth charts. The Apgar score was 0 at 1 min, the neonate was intubated and ventilated, cardiac compressions were performed and adrenaline was administered via an endotracheal tube (ETT). The Apgar score was 3 at 5 min. The umbilical vein was catheterized (UVC) and prostaglandin infusion was commenced. Blood gases from the UVC were: pH = 6.81, pO₂ = 14.3 mm Hg, pCO₂ = 124.9 mm Hg and B.E.(Base Excess) = −17.3 mmol/L. The neonate was transferred to the neonatal intensive care unit (NICU) and 35 min after birth, blood gases from the UVC were: pH = 6.87, pO₂ = 85.9 mm Hg, pCO₂ = 45.6 mm Hg, B.E. = −17.7 mmol/L, HCO₃ = 15.9 mmol/L, pO₂/FiO₂ = 218. On clinical examination, the neonate looked dysmorphic with cardiac thrust displaced to the right, bowel sounds in the left hemithorax and reduced air entry in the right hemithorax on auscultation, scaphoid abdomen, palpable liver, hypospadias, right leukocoria, external anomalies of the ears, hypotonia, absent reflexes, oligodactyly and clinodactyly of the upper limbs, arthrogryposis and club feet (Figure 1 and Figure 2). A chest X-ray revealed the presence of bowel loops in the left hemithorax and aplasia of forearm bones (Figure 3). The brain U/S demonstrated excessive bleeding in the basal ganglia bilaterally. Because of the dysmorphic findings, a chromosomal analysis was performed.

Figure 1:

Dysmorphic features of the patient.

Figure 2:

Dysmorphic features of the patient.

Figure 3:

Chest X-ray of the patient.

Despite mechanical ventilation and continuous infusion of prostaglandin, the newborn deteriorated and passed away 9 h postnatally. One month later, the results of the chromosomal analysis (G-banding karyotype) confirmed trisomy 18.

Discussion

CDH is an abnormality of the integrity of the diaphragm (discontinuity or under-muscularization) which arises during embryonic development (4^th–8^th week), allowing migration of abdominal contents into the chest cavity and resulting in pulmonary hypoplasia. The birth prevalence is 1/3000-5000 live births. The major morbidities associated with CDH are pulmonary, gastrointestinal, neurological, musculoskeletal and hearing loss. Approximately 60% of CDH cases are detected prenatally either by an U/S examination or by a fetal magnetic resonance imaging (MRI) scan.

The key determinants of mortality are: whether the CDH is isolated or complex (10%), co-existence of major anomalies, size of the diaphragm defect, the degree of pulmonary hypoplasia, the severity of pulmonary hypertension in the perinatal period, side of the hernial defect and intrathoracic liver. Mortality from CDH continues to be high, ranging from 20% to 60%. Still, higher mortality occurs when complex CDH is associated with a chromosome abnormality, a single-gene disorder and/or the coexistence of major malformations as we already mentioned. Kadir and Lilja [5], in a single-center observational study, found that, for every 100 g increase in birth weight, the risk of death was reduced by 7% and for every increase in the Apgar score, the risk of death was reduced by 34%. Prenatal diagnosis and intrathoracic liver increased the risk of death by 4.55 and 4.0 times, respectively. Associated malformations were not defined as an independent risk factor in this study [5]. The presence of a CVM makes prognosis of the condition worse [6].

Many genetic causes have been identified during the prenatal diagnosis of fetal CDH. Complete autosomal trisomy in fetal CDH is always associated with additional prenatal morphological abnormalities. Large chromosome deletions and duplication have also been associated with CDH. About 10% of all individuals with CDH have a chromosome abnormality. The most common abnormalities are trisomy 18 and isochromosome 12p [7].

Trisomy 18, also known as Edwards syndrome, is the second most common autosomal trisomy after Down syndrome (trisomy 21). The live born prevalence of trisomy 18 ranges from 1/3600 to 1/10000, with the best overall estimate being 1/8000. The overall prevalence is higher (1/2500–1/2600) due to the high frequency of fetal loss and pregnancy termination after prenatal diagnosis. The prevalence at birth is higher in females than in males (F/M 60.4%) in accordance with the higher rates of fetal losses for males. Neonates with trisomy 18 look dysmorphic on clinical examination. Almost all systems may be affected. Structural heart defects occur in over 90% of infants. Most common cardiac anomalies are ventricular and atrial septal defects, patent ductus arteriosus, polyvalvular disease whereas complex malformations such as DORV are present in about 10% of cases [8], [9].

DORV is a malformation of the conotruncus. In this malformation, both great arteries arise predominantly from the right ventricle [10]. It is a rare anomaly; Hoffman and Kaplan [11] reported an incidence of 157 per million live births, with a high degree of complexity and variation, making accurate diagnosis a challenge for the clinician [11]. Albeit the DORV prevalence diagnosed prenatally (mainly during the 2^nd or 3^rd trimester) is estimated to be 0.46%, it decreases significantly to 0.015–0.02% in live births probably because of pregnancy termination or fetal loss [10].

The association of the two specific major anomalies (CDH and DORV) with trisomy 18, as in the present case report, seems to be rare, especially among live births.

Because the co-existence of CDH and CVMs has important clinical, genetic, and developmental implications, a thorough evaluation should be performed. In addition to multi-organ imaging, genetic consultation may be useful to guide the diagnostic evaluation, especially when dysmorphic facial features are observed. If a syndrome is identified prenatally, the information should be made available to the postnatal specialists.