Edwards syndrome

Etiology and pathogenesis of chromosomal aberration

Edwards syndrome belongs to the group of hereditary fetal developmental anomalies, specifically chromosomal disorders. The syndrome is based on a genomic mutation, which is a change in the chromosome number. Unlike polyploidies and full trisomies of large autosomes, which usually lead to spontaneous abortion in the first trimester, trisomy 18 is a viable variant of aneuploidy.

The primary mechanism of this mutation is impaired meiosis during gametogenesis. A key role is played by the nondisjunction of homologous chromosomes: in anaphase, they move to the same pole, forming an unbalanced gamete with an extra chromosome. An alternative mechanism is anaphase lag, where one of the chromosomes "lags" during cell division.

Depending on the stage at which the failure occurred, two forms of the disease are distinguished:

• Complete form — the mutation occurs in gametes, causing an abnormal karyotype with an additional 18th chromosome to be present in all cells of the body.
• Mosaic form — the mutation arises in somatic cells during early stages of embryogenesis. In this case, the body contains both cell clones with a normal karyotype and those with an abnormal one.

Impact on intrauterine development

Genetic factors, including chromosomal abnormalities, are one of the four main groups of causes of intrauterine growth restriction (IUGR). In IUGR, the frequency of chromosomal anomalies reaches 7–19%, which is significantly higher than general population values.

Regardless of the specific etiology, the presence of a genetic defect triggers a common final pathophysiological mechanism — decreased uteroplacental perfusion. This leads to chronic fetal malnutrition.

The severity of manifestations in Edwards syndrome obeys a fundamental rule of genetics: the larger the volume of genetic material involved in the aberration, the earlier the imbalance manifests in ontogenesis, and the more significant the impairments in physical and mental development. The extra 18th chromosome represents a massive imbalance affecting a vast number of genes.

Multiple congenital anomalies (MCA)

Edwards syndrome clinically manifests as multiple congenital anomalies (MCA). From a molecular perspective, an excess of genetic material disrupts the formation of organ structures by altering the function of proteins critical for morphogenesis:

• transcription factors;
• components of signaling pathways (Hedgehog, Wnt, Notch);
• cell adhesion molecules and extracellular matrix.

This leads to impaired cell proliferation, migration, differentiation, and apoptosis at specific stages of organogenesis. The most common finding in fetuses with Edwards syndrome is congenital heart defects (CHD). They form between the 2nd and 8th weeks of intrauterine development. CHDs in chromosomal abnormalities occur in 10–15% of cases and may include defects in cardiac septation (ventricular or atrial septal defects), great vessel anomalies, and combined defects.

When structural anomalies and CHDs are detected on ultrasound (fetal echocardiography is available from the second trimester), fetal karyotyping is mandatory to confirm the chromosomal nature of the disease.

Class and exam questions

What else to study on this topic

• Classification of congenital heart defects (CHD) and mechanisms of their ontophylogenetic formation
• Comparative characteristics of Edwards, Patau, and Down syndromes
• Molecular mechanisms of teratogenesis and the impact of exogenous factors on the fetus
• The rule of chromosomal imbalance severity
• Multifactorial mechanism of isolated malformations development

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.