**4. Etiopathogenesis of CDH**

#### **4.1 Environmental factors**

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

vascular maldevelopment, and the ventricular dysfunction, the three outstanding pathological features of the anomaly. The surgical repair is generally deferred by consensus among the neonatologists and the surgeons. The management is more complicated if CDH is associated with other organ anomalies, which might make the outcome worse. CDH is one of the most challenging morbidities in the neonates. In this article, an evidence based overview of the current status of the disease entity

The reported prevalence of CDH varies among studies [2–5]. The European Surveillance of Congenital Anomalies (EUROCAT) registry data analysis (1980- 2009) has described the prevalence to be 2.3 per 10,000 births for all-inclusive and 1.6 per 10,000 for isolated cases [6]. Balayla *et al*. reported an incidence of 1.93 per 10,000 births in the United States [7]. The variability in the reported prevalence is due to differences in the studied geographical population, data collection methodologies, inclusion and exclusion criteria, case ascertainment and hidden mortality [8]. A decreasing trend in the live births with CDH has been reported, most likely due to an increasing number of termination of pregnancies with antenatal diagnosis of fetuses with CDH [5, 6]. Overall, the survival rate in CDH, although variable among centers, is >70% and has consistently improved over time [9, 10]. A nonsignificant improvement in the survival of CDH cases which are complicated with major cardiovascular or chromosomal anomalies has been recently reported [10]. The implementation of the standardized management protocols has improved the survival rate from 67% to 88% [11]. Overall, the evaluation of epidemiology and risk factors for CDH is arduous due to the heterogeneity among the studies.

CDH is more common in males [7]. The reports regarding the association of high maternal age with increased risk of CDH are conflicting [5–7, 12]. Pre gestational hypertension [5, 13] and alcohol abuse are other proposed maternal risk factors [7, 13, 14]. The impacts of ethnicity, race, maternal tobacco use and pre gestational diabetes on the risk for CDH are unclear and need further research, although a slightly lower occurrence in blacks has been documented. The identification of modifiable antenatal risk factors help in deciding the direction of prenatal

Congenital diaphragmatic defects (CDD) are classified as posterolateral (Bochdalek, 70-75%) and non-posterolateral according to the location. Nonposterolateral hernias can be retrosternal (Morgagni-Larrey, 23-28%) or central (2-7%), that involves the non-muscular or central tendinous portion of the diaphragm [15]. This anatomical classification has drawbacks as the actual site of lesion may not be easy to discern. Around 85% of the posterolateral CDH are on the left, while 10% are right sided and 5% bilateral. The diaphragmatic eventration is a rare anomaly in which a part or whole of the hemi diaphragm is abnormally elevated into the thoracic cavity, as the normal diaphragmatic musculature is partly or fully replaced by a thin fibro membranous membrane [15], allowing the abdominal viscera to protrude upwards. In order to elucidate the developmental pathways of diaphragmatic defects more accurately, Ackerman et al developed a phenotype worksheet to capture the precise morphological data on CDD by retrospectively analyzing autopsies of 181 cases [16]. They proposed a new classification system

screening and thus the prevention of CDH.

**3. Classification of CDH**

**120**

is provided.

**2. Epidemiology**

Environmental factors contributing to CDH are not well investigated. Maternal vitamin A deficiency, nitrofen treatment and retinoid receptor knock-out in animal model are reported to result in CDH in their offsprings, suggesting a role of retinoid signaling pathway in the pathogenesis [18]. Similar effects are seen in WT1 and COUP-TFII mutant mouse models. Beurskens et al found a significantly higher risk of CDH in the infants born to mothers who had low vitamin A intake during pregnancy (Odds ratio, 7.2; 95% confidence interval, 1.5-34.4; p = 0.01)[19]. The cord blood in neonates with CDH is reported to have low retinol and retinol-binding protein levels. Thalidomide and quinine have also been implicated as possible causes of CDH [20].

### **4.2 Genetics of CDH**

CDH is genetically heterogeneous although can be monogenic. A genetic cause is found in 30% of the cases, even though most cases are sporadic and about 1-2% familial [21]. The application of the next generation sequencing technologies, e.g. DNA array and whole genome sequencing has contributed to the identification of cases with genetic etiology.

Chromosomal anomalies account for about 10% of the CDH cases. The common chromosomal aneuploidies associated with CDH are trisomy 18, 13 and 21. Morgagni hernia is more frequently found in trisomy 21 than Bochdalek hernia. Pallister Killian syndrome (PKS), characterized by mosaic tetrasomy 12p is a common chromosomal anomaly associated with CDH and occurs sporadically. The karyotype in PKS is often found to be normal due to a tissue specific distribution of chromosome i12p and reduced yield with culture aging [22, 23]. Establishing diagnosis in such cases depends on the tissue examined and genetic test used [24]. Isochromosome 12p is rarely isolated from cord blood lymphocytes, whereas its yield from the skin fibroblast is close to 100% [25]. Also, the chorionic villus sampling may miss mosaicism, while detection rate of amniocentesis is nearly 90% [23, 26]. Chromosome 12p targeted-FISH, array comparative genomic hybridization (aCGH) or other newer genetic technologies should be used to prevent misdiagnosis in the condition [24, 27]. The availability of information regarding genetic etiology equips the clinicians with better understanding of the prognosis for discussion with the parents.

Some of the common monogenic syndromes associated with CDH are Cornelia de Lange, Donnai Barrow and Simpson-Golabi-Behmel, while, others, like Fryn

syndrome, Pentalogy of Cantrell and thoracoabdominal syndrome are of unknown etiopathogenesis. Fryn syndrome, a close differential of PKS, is a clinical diagnosis and is associated with CDH in 80% of the cases. Other features of this syndrome are nail hypoplasia, high arched or cleft palate and a characteristic facies that is similar to PKS. Excellent reviews on genetics in CDH are available elsewhere [21, 28, 29].
