Obstetrics and Gynecology - A.M. Gromova 2000

Medical and Genetic Counseling in Obstetrics
Hereditary Diseases and Congenital Malformations
Genetic Congenital Malformations

Genetic developmental defects are represented by various isolated congenital anomalies and syndromes. Their occurrence is caused by the following factors:

1. Alteration of hereditary structures (genetic Variability):

a) combinative;

b) mutational.

2. Endocrine disorders.

3. Overripening of the oocyte.

4. Age-related changes in parents.

Genetic variability is one of the major causes of Congenital Malformations (90%). Combinative variability consists in acquiring new Gene combinations within the genotype.

This is achieved through such processes as:

- independent assortment of Chromosomes during Meiosis;

- random combination of chromosomes during Fertilization;

- gene recombination due to Crossing-over.

Mutations are alterations caused by the reorganization of reproductive structures and Changes in the genetic apparatus. There are three main levels of mutations: gene, chromosomal, and genomic.

Gene Mutations involve changes in the Internal Structure of individual genes due to the transition of some alleles into others through the substitution, deletion, or insertion of individual NUCLEOTIDES within the DNA strand.

Monogenic Disorders are most commonly caused by enzymatic defects (such as phenylketonuria, cystic fibrosis, lactosuria, homocystinuria, hypothyroidism, and many others). They are inherited in an autosomal dominant, autosomal recessive, or sex-linked manner.

Polygenic (multifactorial) disorders result from a combination of genetic and non-genetic factors (including neural tube defects, cleft lip and palate, congenital hip dislocation, Congenital Heart defects, and pyloric stenosis). Unlike Monogenic Diseases, the risk of giving birth to a child with such a defect increases with the number of affected relatives. For certain conditions, the incidence depends on sex (congenital hip dislocation is more common in girls, whereas pyloric stenosis is more frequent in boys).

Chromosomal Disorders occur with a frequency of 6 per 1,000 fetuses.

Chromosomal mutations are structural alterations of chromosomes resulting from translocation, deletion, duplication, or inversion. Chromosomal aberrations can be balanced (not accompanied by significant phenotypic changes) and unbalanced (accompanied by marked phenotypic changes). An example of the latter is cri-du-chat syndrome (deletion of the terminal segment of the short arm of chromosome 5). 100% of affected individuals exhibit mental retardation, Central Nervous system anomalies, congenital heart defects, and a characteristic cry. Additional features may include micrognathia, ocular abnormalities, and hernias.

Genomic mutations involve alterations in chromosome number, which are usually accompanied by significant phenotypic changes. They lead either to spontaneous abortions or to severe multiple congenital malformations (CMs). In the first trimester, 50–60% of miscarriages are caused by chromosomal aberrations (autosomal trisomies, monosomies, polyploidies). Structural anomalies in aborted fetuses account for only 5%.

Congenital malformations caused by autosomal genomic mutations are typically accompanied by severe central nervous system impairment (mental retardation) and damage to other Organs. Examples include Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13). Syndromes caused by alterations in sex chromosome number, such as Klinefelter syndrome (47,XXY) and Turner syndrome (45,X0), are not accompanied by severe central nervous system disorders.

Mutations can be spontaneous (resulting from metabolic disturbances in Cells, Replication errors, or natural Background radiation) or induced (caused by external factors, known as mutagens).

Endocrine disorders and metabolic defects can exert both mutagenic and teratogenic effects. For instance, maternal hypothyroidism leads to enzymatic cretinism in the fetus; phenylketonuria results in mental retardation, congenital heart defects, and microcephaly; and Insulin-dependent forms of Diabetes Mellitus cause diabetic fetopathies (mental retardation in 15%, cardiovascular defects in 30%, and skeletal anomalies in 40%). Furthermore, caudal Dysplasia occurs 227 times more frequently in fetuses of mothers with diabetes mellitus compared to the general population.

Gamete overripening encompasses a complex of changes occurring in Gametes from the time of their complete maturation until fertilization. Most commonly, this arises from the desynchronization of ovulation and fertilization, resulting either from prolonged retention of spermatozoa in the female reproductive tract or from intrafollicular overripening of the oocyte. The primary mechanism underlying gamete overripening is nondisjunction of chromosomes.

Age-related gamete senescence leads to an increased frequency of mutations. This is associated with a decline in The activity of various Enzymes and Hormones, resulting in impaired Cell/23.html">DNA Repair Mechanisms and defective nidation. After the age of 35, a woman's probability of having a child with a chromosomal pathology more than doubles to 1 in 185 (compared to 1 in 510 under the age of 30). Between the ages of 40 and 44, this probability rises to 1 in 63, and after 45, it reaches 1 in 24—meaning it is 21 times higher than before the age of 35.