Keywords pulmonary hypoplasia - congenital diaphragmatic hernia - myelomeningocele - thoracic
dysplasia - persistent pulmonary hypertension - Chiari malformation - skeletal deformity
The prognosis of patients with congenital diaphragmatic hernia (CDH) has improved
thanks to advanced perinatal management including prenatal diagnosis, scheduled delivery,
and gentle ventilation. The most recent nationwide survey in Japan (from January 2006
to December 2010) reported that the survival rate of isolated CDH patients improved
to 80%.[1 ] Nonetheless, fatal CDH cases due to severe pulmonary hypoplasia and persistent pulmonary
hypertension of the newborn (PPHN) still exist.[1 ]
Several studies[1 ] have reported a high mortality rate for patients with complex, nonisolated or syndromic
CDH. The prognosis of patients with CDH complicated with cardiovascular malformation
and musculoskeletal or craniofacial defects is poorer than that of patients with isolated
CDH.[2 ]
[3 ] In some cases, pulmonary hypoplasia caused by other congenital disorders was associated
with a poorer prognosis.[4 ]
[5 ]
We herein report a very rare case of fatal CDH associated with thoracic myelomeningocele
(MMC) and thoracic dysplasia.
Case Presentation
A 23-year-old pregnant woman (gravida 2, para 0) was referred to our hospital at 21
weeks of gestation due to fetal hydrocephalus, MMC, and cardiac malposition. She had
no history of infection, medication, or any other diseases during pregnancy. She also
had no family history of congenital disease. There was no consanguineous relationship.
Prenatal sonographic findings at 22 weeks of gestational age revealed only fetal thoracic
MMC with enlargement of the anterior and posterior horns of the bilateral ventricles,
left scoliosis narrowing the left thoracic space, and dislocation of the fetal heart
into the right thorax. The amniotic fluid volume was normal. No further fetal diagnostic
tests including a fetal MRI were conducted due to the family's poor economic situation.
A male baby was delivered at 36 weeks and 6 days of gestation by elective cesarean
section in accordance with our early delivery protocol for prenatally diagnosed MMC
cases with severe hydrocephalus to prevent the progression of the hydrocephalus. His
birth weight was 2,996 g (z score; +1.2). At birth, he presented with generalized
cyanosis and bradycardia and was unable to breathe on his own. He was immediately
intubated and placed on positive-pressure ventilation with 100% oxygen. His heart
rate recovered to 130 bpm through resuscitation, but the hypoxia persisted.
His height and head circumference were 44.0 cm (z score; –1.4) and 42.0 cm (z score;
+7.5), respectively. He had an enlarged head circumference, low-set ears, depressed
nasal root, short trunk, posterior thoracic MMC, and deformity of the lower limbs.
His blood gas analysis on admission to the neonatal intensive care unit (NICU) showed
severe mixed acidosis (pH 6.982; PCO2 80.3 mm Hg; and BE –13.6 mmol/L) but the complete blood count and blood chemistry
were normal. His chromosomes showed the normal karyotype. Genetic analysis with exome
sequencing disclosed no abnormalities. A chest plain radiograph demonstrated herniation
of the intestines into the left thoracic cavity, several deformed vertebrae and left
ribs, and scoliosis ([Fig. 1A ]). Echocardiography showed no structural anomalies, but there was a right-to-left
shunt through the ductus arteriosus and the foramen ovale. The McGoon index[6 ] was 1.17. In addition, a brain ultrasound examination showed severe hydrocephalus.
Although we applied high-frequency oscillatory ventilation, inhaled nitric oxide therapy,
and vasoactive drugs, his hypoxia did not improve. At about 30 hours of age, the patient
died of respiratory failure due to PPHN.
Fig. 1 Chest plain radiography and computed tomography (CT). (A ) Chest plain radiography demonstrated herniation of the intestine into the left thoracic
cavity, deformity of several left vertebrae and ribs, and scoliosis. (B ) Brain CT showed hydrocephalus and Chiari malformation type II.
A postmortem computed tomography (CT) showed severe hydrocephalus, Chiari malformation
type II, left CDH without herniation of the liver and stomach into the chest cavity,
agenesis of the left kidney, and a multiple segmentation anomaly from T4 to T12 ([Fig. 1B ]). Fusion and deformity of several left ribs and short stature were observed ([Figs. 2A ] and [2B ]). The overall skeletal deformities were similar to those seen in spondylothoracic
dysostosis. We considered Jarcho-Levin syndrome in the differential diagnosis. However,
the severity of the rib fusion was insufficient for a definitive diagnosis of this
syndrome.
Fig. 2 Autopsy imaging . (A ) Postmortem computed tomography showed multiple segmentation anomalies from T4 to
T12 and deformity of the lower limbs. (B ) Fusion of several left ribs and deformities was seen.
The autopsy findings included Bochdalek hernia-type CDH and severe pulmonary hypoplasia.
The size of the defect in the diaphragm was 22 × 15 mm (type B).[5 ] His intestinal tract (from the duodenum to ascending colon) and spleen invaded the
thoracic cavity ([Fig. 3A ]). The right lung wet weight was 11.4 g (expected right lung wet weight adjusted
by body weight derived from the autopsy database of Japanese sudden infant death syndrome
diagnosed pathologically: 37.9 g) and the left lung wet weight was 3.2 g (expected
left lung wet weight: 27.9 g). Both lungs showed normal lobulation ([Fig. 3B ]). The right kidney was 20.3 g (expected right kidney weight: 17.9 g) and agenesis
of the left kidney was present. We obtained parental consent to use the patient's
data in our report.
Fig. 3 Autopsy findings. (A ) The neonate had left congenital diaphragmatic hernia without herniation of the liver
(a) into the thoracic space. The intestine (b), colon (c), and spleen invaded the
thoracic cavity. The heart (d) had shifted to the right side of the chest cavity.
(B ) The right lung (R) wet weight was 11.4 g and the left lung (L) wet weight was 3.2
g. Both lungs had normal lobulation.
Discussion
We presented a very rare case of fatal pulmonary hypoplasia with CDH, MMC, and thoracic
dysplasia and discussed the mechanisms leading to fatal lung hypoplasia in this infant.
Currently, there are several systems for scoring the severity and predicting the prognosis
of patients with isolated CDH. For example, Kitano's classification divides patients
with isolated CDH into three groups according to liver and stomach position.[7 ] Based on this classification, CDH without herniation of the liver and stomach into
the thoracic cavity has the most favorable prognosis (survival rate: 87%). Importantly,
this classification is designed for isolated CDH and if applied to nonisolated CDH
such as the present case, it would assess the prognosis as good. Another classification
is that of Morini et al[5 ] based on the defect size in the diaphragm muscles. Under this system, our case would
have been classified as type B, that is, a case in which the size of the defect is
less than half the size of the left diaphragm. Although the prognosis of type B is
usually not very poor, the outcome of our case was otherwise.
Because the CDH went unnoticed in our patient, we did not have data on his pulmonary
hypoplasia in the prenatal diagnosis. We, therefore, calculated the score using data
from his postmortem CT scans. The observed/expected lung area to head circumference
ratio (o/e LHR) was 24% (<25% for severe cases), although this might have been underestimated
due to his severe hydrocephalus. After adjusting the patient's head circumference
by reference to the normal head circumference for gestational age (32.6 cm), we arrived
at an adjusted o/e LHR of 31% (normal >45%).
In the present case, we hypothesized that two mechanisms were associated with the
fatal and severe pulmonary hypoplasia. First, the herniation of the abdominal organs
(the digestive tract and spleen) into the thoracic space would have inhibited lung
growth by occupying the thoracic space as usually occurs in CDH. Second, the thoracic
dysplasia due to scoliosis to the left side and the deformities of the vertebrae and
ribs disrupted the growth of the thoracic cavity and lungs during the fetal period.
As a result, both sides of the thoracic cavity were small, with the herniated intestine
compressing the left lung and causing the displaced heart in turn to compress the
right lung. This situation severely inhibited lung growth. Furthermore, the fetal
breathing movements may have been suppressed by thoracic MMC, Chiari malformation
type II, and severe hydrocephalus, although neither a recording of fetal breathing
nor the bishop score was available for this case. Hydrocephalus and Chiari malformation
type II may impair the function of the respiratory center or cranial nerves, which
regulate the respiratory pattern and the laryngeal muscles, respectively.[8 ] Additionally, a peripheral nerve injury due to thoracic MMC in our patient could
have impaired the function of accessory respiratory muscles. These mechanisms could
then have decreased the fetal breathing movement and the capacity to maintain lung
water, further inhibiting normal lung development.
Several reports have discussed the prognosis of infants with a combination of these
anomalies.
The prevalence of the combination of CDH and MMC was reportedly 4.3% among 116 CDH
cases.[3 ] While there are only a few reports of infants with CDH complicated with thoracic
MMC and thoracic deformities who experienced fatal respiratory failure with severe
pulmonary hypoplasia, the findings suggest that the combination of these three anomalies
increases the severity of respiratory failure.[9 ] Recently, a case report on right-sided CDH with MMC was published.[10 ]
Of the various types of MMC, thoracic MMC has the highest mortality rate.[11 ] Although the predominant cause of death was infection, in 37% of patients the cause
of death was uncertain. On the other hand, the prevalence of scoliosis is reportedly
53% in MMC patients; however, the number of severe cases has not been reported.[12 ]
Severe spondylothoracic dysostosis, a form of thoracic dysplasia, is reportedly a
frequent cause of pulmonary dysplasia in itself. Of 27 patients with severe spondylothoracic
dysostosis, 44% suffered from respiratory insufficiency and died within 6 months.
There are several limitations to this study. First, because the neonate had multiple
abnormalities, there was a possibility that the severe pulmonary hypoplasia and severe
PPHN were originally caused by genetic anomalies. Second, there is no definition of
thoracic hypoplasia. Therefore, we were unable to predict the extent to which the
thoracic dysplasia due to scoliosis and the deformities of the vertebrae and ribs
may have influenced lung growth and development. Finally, there were no data indicating
decreased fetal breathing movements or the capacity to maintain lung water. Our decision
to perform late preterm elective delivery on account of the severe hydrocephalus may
also have increased the risk of respiratory distress in this case.
In conclusion, we experienced a case of fatal pulmonary hypoplasia with CDH, thoracic
MMC, and thoracic dysplasia. The combination of several congenital anomalies may have
had a negative impact on fetal lung growth, leading to severe pulmonary hypoplasia.
Therefore, when assessing the prognosis of neonates with CDH, we should take into
account the adverse effects of complicated anomalies on lung development.
