Congenital Diaphragmatic Hernia

Epidemiology and Background

Congenital diaphragmatic hernia (CDH) is a developmental anomaly with a prevalence ranging between 1 and 4 in 10,000 births, which means that in Europe, around 2000 children are born with this condition every year. Despite being relatively uncommon, CDH is a major clinical concern inside the realm of neonatology, with important implications for diagnosis, management and prognosis. Although medical and surgical management have improved the outcome of this condition, CDH remains associated with high mortality and significant morbidity.

A primary characteristic of CDH is that the diaphragm fails to form properly during embryogenesis. Normally, the diaphragm develops to form a continuous sheet that completely separates the thoracic and abdominal cavities before the major period of internal organ growth. In the case of CDH, a significant proportion of the diaphragm is absent. The defect is usually on the left side (85%) but can also occur on the right (12%–15%) or bilaterally. In some rare instances, a true agenesis of the hemidiaphragm is present, but in most cases, the defect is limited to the posterolateral region of the diaphragm (referred to as Bochdalek hernia). The anterior (Morgagni hernia; 25%–30%) or central regions (2%–5%) can also be affected. Less often, the diaphragm is present but thinned and devoid of muscular fibres (diaphragmatic eventration).

The diaphragmatic defect allows herniation of abdominal viscera into the thorax, where they compete for the space normally reserved to accommodate the growing lungs. When the defect is located on the left side, the thorax may contain small and large bowel, the spleen, the stomach, the left lobe of the liver and, occasionally, the kidney. Right-sided CDHs virtually always contain part of the right lobe of the liver and sometimes the bowel, kidney, or both. The loss of a continuous diaphragmatic muscle also impairs fetal breathing movements that are necessary for proper stretch-induced lung maturation.

Lungs of fetuses with CDH display variable degrees of lung hypoplasia, with impairment of both airway and vascular maturation. These changes become symptomatic immediately after birth, when neonates have variable degrees of respiratory insufficiency and persistent pulmonary hypertension (PPH), which is often resistant to inhaled nitric oxide (iNO).

In 50% to 60% of cases, the diaphragmatic defect and lung hypoplasia are the only significant anomalies. In the remaining cases, there are major nonpulmonary congenital anomalies. Cardiovascular defects such as ventricular septal defects, cardiac outflow anomalies (tetralogy of Fallot, double outlet right ventricle, transposition of the great vessels and others) and abnormal great vessels (right aortic arch, double aortic arch, truncus arteriosus, abnormal subclavian arteries and others) are the most common associated anomalies, found in about one third of patients with CDH. Left ventricular hypoplasia has also been described, yet its occurrence and clinical relevance are debated. Musculoskeletal defects such as anomalies of the limbs or of the number and shape of the vertebral bodies or ribs, neural tube defects, abdominal wall defects, craniofacial defects or urinary tract anomalies have also been reported. Associated malformations are sometimes components of Pallister-Killian and Fryns syndromes; Ghersoni-Baruch syndrome; Wilms tumour, aniridia, genitourinary anomalies, and mental retardation (WAGR); Denys-Drash; and other syndromes. Some chromosomal anomalies, such as 9p tetrasomy, have CDH as part of their spectrum. For further information we refer to the excellent review by Slavotinek and colleagues.

Finally, the presence of the intestine in the thorax during late fetal development causes malrotation, malfixation, or both, which can further complicate the disease.

Aetiology and Pathogenesis

The causes of CDH are largely unknown, although exposure to teratogens or pharmacologic agents has been suggested. In particular, phenmetrazine, thalidomide, quinine, nitrofen and vitamin A deficiency have been linked to this disease. In the classical view, the defect in CDH occurs first in the muscular part of the diaphragm. However, studies in rats have suggested that CDH is a primary lung pathology, even in humans. Keijzer and colleagues proposed the ‘dual-hit hypothesis’, that is, that two independent events cause the major features seen in CDH. These hits disturb normal lung development (first hit) and diaphragm formation (second hit). Data from animal studies confirm this hypothesis: in the toxic nitrofen model in rats, abnormalities in the ipsilateral as well as the contralateral lung are present already before the development of the diaphragm.

Another theory is based on the hypothesis that nonclosure of the pleuroperitoneal canals would be caused by a defect in the pleuroperitoneal folds (PPFs), the source of diaphragmatic cells. Of interest, the diaphragmatic defect in the nitrofen model is located more medial than could be expected from nonclosure of these canals. Therefore it has been proposed that the origin of the diaphragmatic defect lies in the amuscular mesenchymal precursor cells of the diaphragm, which are also derived from the PPFs. This theory is based on the observation that although the migration of muscular precursors is not disturbed, a defect occurs in regions of the underlying mesenchymal substratum of the PPF. This would subsequently contribute to the defective region in CDH.

Finally, an involvement of the retinoid signalling pathway is likely in CDH. Both animal and clinical studies have shown that retinol and retinol-binding proteins are decreased in newborns with this malformation. Moreover, some of the genes involved in the pathogenesis of human CDH are tightly related to retinoid signalling.