Practice points
- •
Aneuploidies and chromosome copy number variants are present in 10–35% of CDH cases and are more frequent in
Congenital diaphragmatic hernia (CDH) occurs in 1 in 3000 live births, accounting for 8% of all birth defects and 1–2% of infant mortality, making it one of the most prevalent and lethal congenital anomalies [1], [2], [3]. The diaphragm develops during the 4th–8th week of gestation, and the hernia is thought to occur when the pleuroperitoneal folds and septum transversum fail to converge and fuse. Posterior lateral hernias (Bodaleck) account for >95% of neonatal diagnoses with 85% occurring on the left side [1], [4]. Anterior retrosternal or parasternal hernias (Morgagni) account for ∼2% of all CDH cases. Other rare types of hernias include an anterior hernia often associated with Pentalogy of Cantrell and a central hernia which involves a defect in the central tendon. Diaphragm eventration resulting from incomplete muscularization of the diaphragm is also included within the spectrum of CDH. Approximately 50–80% of CDHs are diagnosed in the prenatal period when the liver and intestines are visualized in the chest with a malpositioned heart. CDH may occur as an isolated defect, but ∼40% of CDH cases are non-isolated and have at least one additional anomaly [5], [6]. The most frequent co-occurring defect is congenital heart disease (CHD) which is present in ∼20% of patients [4], [6]. Birth defects of all other systems have also been described in CDH cases. In some cases, the constellation of birth defects is associated with a specific syndrome and may provide insight into the genetic etiology. More than 50 different genetic causes have been associated with CDH. Most in non-isolated cases but genetic etiologies are increasingly being identified in isolated CDH cases. We review the most widespread chromosomal and monogenetic causes with CDH as a recognized feature.
Complete or mosaic chromosome aneuploidies, large chromosome deletions/duplications, and complex chromosome rearrangements identifiable by karyotype are present in 10–35% of CDH cases and occur at greatest frequency in non-isolated, prenatally diagnosed cases [2], [6], [7], [8], [9], [10], [11]. An additional 3.5–13% of cases without identifiable karyotype abnormalities have copy number variants (CNVs) including microdeletions or microduplications identifiable by chromosome microarray analysis,
It is clear that there is significant heterogeneity in the cause of CDH and that we are in a period of rapid expansion of our knowledge of the genetics of CDH. As we define the spectrum of genes associated with CDH, we will be able to define common molecular causes of CDH and define the clinical syndromes associated with these genes to inform prognosis and guide treatment. Aneuploidies and chromosome copy number variants are present in 10–35% of CDH cases and are more frequent inPractice points
This work was supported by National Institute of Health grant R01 HD057036 (W.K.C., principal investigator).