Medical Genetics - V. M. Zaporozhan 2005

Chromosomal Disorders
Prenatal Diagnosis of Chromosomal Abnormalities

Pathology associated with a chromosomal imbalance causes various developmental disorders in affected individuals and may be linked not only to multiple Congenital Malformations, but also to mental and physical disability, sexual development disorders, Infertility, and Miscarriage. Treatment for most of these patients has low efficacy, and the prognosis is unfavorable. Therefore, modern healthcare is seeing the rapid development of Methods for the prenatal Diagnosis of Chromosomal diseases. Prenatal diagnosis refers to the detection of hereditary disorders and congenital malformations during Pregnancy. If a chromosomal abnormality is detected in the fetus, pregnancy termination is typically recommended.

METHODS OF PRENATAL DIAGNOSIS

They are classified as follows:

a) non-invasive (ultrasound, measurement of substances in the pregnant woman's Blood serum known as maternal serum markers: the ß-fraction of human chorionic gonadotropin (βhCG), pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), total human chorionic gonadotropin (hCG), and unconjugated estriol);

б) invasive (chorionic villus sampling, amniocentesis, cordocentesis, and placentocentesis, followed by cytogenetic Diagnostics).

The vast majority of chromosomal syndromes originate from de novo sporadic Mutations. The risk of giving birth to a child with chromosomal trisomies increases significantly with maternal age. In many countries, women over 35 years of age are referred for invasive prenatal testing without prior non-invasive screening. However, pregnant women over 35 account for no more than 9% of the general population. Age as an isolated indication for prenatal diagnosis allows for the detection of no more than 2% of life-limiting chromosomal and genomic mutations. Overall, children with chromosomal diseases and syndromes are predominantly born to young mothers; therefore, screening for chromosomal abnormalities during pregnancy using non-Invasive Methods is of paramount importance.

The most effective approach is combined prenatal screening for Chromosomal Disorders (a combination of ultrasound screening and the measurement of maternal serum markers), which is carried out in two stages.

Stage One: Screening

in the First Trimester of Pregnancy

At 10-14 weeks, ultrasound screening is performed, and PAPP-A (pregnancy-associated plasma protein A) and the ß-fraction of human chorionic gonadotropin (βhCG) are measured. A highly specific ultrasound marker of fetal pathology in the first trimester is the measurement of the fetal nuchal translucency (NT) thickness. An increase in this parameter above 2.5 mm is indicative of chromosomal trisomies, monosomy X, and polyploidy, serving as an indication for invasive diagnostics. Notably, this is observed in only 5% of fetuses with a normal karyotype. The second first-trimester ultrasound marker is the presence of the fetal Nasal bone, the absence of which indicates a high risk of Down syndrome. During this period, Changes in the concentration of serum markers also point to chromosomal pathology. For instance, Down syndrome is characterized by a decreased PAPP-A concentration and an elevated ßhCG level. In Edwards syndrome, both PAPP-A and ßhCG levels are decreased.

Stage Two: Second-Trimester Screening

At 15-20 weeks, ultrasound screening is performed along with the measurement of two serum markers: AFP and hCG. In some countries, a triple biochemical test is used, which measures AFP, hCG, and unconjugated estriol.

The normal concentration of AFP in the serum of pregnant women at 15-20 weeks of gestation ranges from 0.5 to 2.5 MoM, and hCG is up to 2.0 MoM. An AFP level below 0.5 MoM combined with an hCG level above 2.0 MoM is characteristic of a pregnancy with fetal Down syndrome. Changes in serum markers for certain fetal chromosomal diseases are presented in Table 5.8.

The combined use of ultrasound and serum markers, along with computerized data Processing that takes into account the mother's age, body weight, and gestational age, makes it possible to detect up to 87% of fetuses with chromosomal abnormalities in the first trimester and 60-70% In the second trimester. However, these methods yield a small percentage of false-positive results. Therefore, if screening tests reveal signs of a chromosomal abnormality, invasive prenatal testing should be performed to determine the definitive fetal karyotype.

The main method of targeted invasive prenatal diagnosis in the first trimester is transcervical (less commonly, transabdominal) chorionic villus sampling, followed by fetal karyotyping. In the second trimester, amniocentesis, placentocentesis, and cordocentesis are performed for this purpose.

INDICATIONS FOR INVASIVE DIAGNOSIS OF CHROMOSOMAL PATHOLOGY:

1) maternal age under 18 and over 35 years (non-invasive first-trimester screening significantly reduces The Need for testing in this age group);

2) having a child (fetus) with a chromosomal disorder or multiple malformations in the family history;

3) presence of chromosomal and genomic mutations in the parents;

4) signs of chromosomal pathology detected during prenatal screening.