Developmental Anomalies

These are also known as congenital disorders, congenital malformations or birth defects. They develop prenatally during embryonic development and may be identified before or after birth. They could be structural anomalies or functional abnormalities. Structural anomalies includes anomalies such as cleft lip, open neural tube and heart defects. Functional anomalies include conditions such as phenylketonuria. Congenital anomalies are caused by several factors which are classified into environmental factors and genetic factors, known as teratogenic factors. Genetic factors include abnormalities in genes and anomalies of chromosomes.

Fig. 9.1. The illustration shows the outlines of classification of factors causing developmental anomalies.

Teratogenic Environmental Factors

Teratogens are substances which interfere with the normal embryonic development and cause congenital anomalies. Environmental teratogens include toxic substances and chemicals such as drugs and alcohol, in addition to infectious agents. Teratogens are often inhaled or ingested during pregnancy. The severity of teratogenicity depends on the type of the substance, the dose, duration of the exposure and age of the embryo or fetus at the time of exposure to the teratogen. Teratogens account for about 5% of congenital anomalies. Certain medications including some of the over the counter (OTC) medications are considered teratogenic, most important are vitamin A, antimicrobial drugs, antiepileptic drugs, anticoagulants and hormones.

Fig. 9.2. The histogram the percentages of the major classes of teratogens. It is apparent that in about 50% of the cases, the causes are unknown.

Teratogenic environmental toxic chemicals include lead, mercury and other heavy metal contaminating manufacturing facilities. Such factors may cause anomalies such as cleft lip, cleft palate, spina bifida and heart defects.

Infectious teratogenic agents include viruses, bacteria and parasites. Most renowned of these agents are the cytomegalovirus, the herpes simplex virus, the rubella virus, the chicken box virus, HIV, hepatitis C virus, streptococci and listeria bacteria, in addition to the toxoplasma parasite.

Radiation is another important teratogenic environmental factors. High-dose radiation exposure may lead to growth retardation, microcephaly, developmental delay, preterm birth, and abortion. During the first two weeks of embryonic development, radiation could be lethal to the embryo and causes miscarriage.

Exposure to teratogens is harmful throughout pregnancy but is more harmful during the first eight weeks of pregnancy because organogenesis takes place mainly during this period,  making the developing embryo and fetus more sensitive to the harmful effects of teratogens. Radiation may break strands of the DNA molecule and may interfere with the normal segregation of duplicate sets of chromosomes to daughter cells at the time of cell division, thereby altering the structure and number of chromosomes in daughter cells

Fig. 9.3. The illustration shows the various types of teratogenic microorganisms.

Teratogenic Genetic Factors

Genetic causes of developmental anomalies fall into three general categories which are single-gene defects, chromosomal abnormalities and multifactorial influences. Prenatal environment can play a major role in the development of defects in all three categories, especially those linked to multifactorial causes.

Single Gene Congenital Disorders

These are congenital disorders that are caused by single gene defects. Some of the more common single-gene disorders include cystic fibrosis, hemochromatosis, Tay-Sachs, and sickle cell anemia. Mutations in the cystic fibrosis gene (CFTR gene) cause cystic fibrosis, which affects the chloride channels of cells. The CFTR gene is responsible for making the channel that transports chloride ions into and out of cells. Hemochromatosis is a condition where iron levels in the body build up over years; it is of two types.  Type-1 hemochromatosis results from mutations in the HFE gene, whereas type-2 hemochromatosis results from mutations in either the HJV or HAMP gene. Tay-Sachs disease is a rare hereditary genetic disorder caused by the absence of the enzyme which breaks down gangliosides which are fatty substances. The lack of this enzyme, which is caused by a mutant HEXA gene, results in the build up to toxic levels of gangliosides in the brain and spinal cord thus affecting the normal functioning of neurons. Sickle cell anemia affects hemoglobin and the shape of red blood cells (RBCs) rendering them from the normal flexible discoid red blood cells into rigid, sickle-shaped cells. It is caused by a mutation in the hemoglobin beta gene (HBB).

Fig. 9.4. The illustration shows the change in the shapes of RBCs in patients with sickle cell anemia. The normal RBCs on the left are discoid where RBCs of sickle cell anemia patients (right) are sickle-shaped.

Congenital Chromosomal Disorders

These congenital anomalies are caused by defects affecting whole genes are regards to their structure or numbers.

The Chromosomes

The chromosome is slender rodlike structure made of a single molecule of DNA and associated proteins; chromosomes carry the genomic information from an individual to his progeny and from a cell to its daughter cells. DNA strands carry the genetic information in the genes they contains, whereas the proteins present in the strands protect the DNA strands and regulate their activities. In the eukaryotic cells of humans and other mammals, chromosomes reside within the cell nucleus. Humans possess twenty-three pairs of chromosomes in the form of one pair of sex chromosomes (XX or XY) and twenty-two pairs of autosomes, making a total of 46 single chromosomes. One chromosomes in each pair of chromosomes is obtained from the mother and the other from the father. Accordingly, each individual has twenty-three chromosomes obtained from the father and twenty-three chromosomes from the father; this means that newborns inherit half of their genes from their mother and the other half from the father. Chromosomes are visible under the light microscope but only during cell division; in non-dividing cells, they stretch out into very thin threads that are not visible as individual entities but together constitute what is known as the nuclear chromatin.

Chromosomes are best seen in the metaphase of dividing cells. The metaphase chromosome consists of two identical rod-shaped sister chromatids joined together at a point called the centromere. The chromatids are young chromosomes attached to each other; they separate from each other in the next phase of cell division, the anaphase. Once they separate from each other, the chromatid become known as chromosomes. Each chromosome has two arms, one on either side of the centromere. The shorter arm of the two is called the P-arm whereas the longer one is known as the Q-arm. The terminal region of the chromosomes is called the telomere. In some chromosomes the centromere is present exactly in the middle of the chromosome; such a chromosome is called a metameric chromosome, i.e., metameric chromosomes have two arms of the same length. When the centromere is slightly displaced from the center of the chromosome, it is called a submetacentric chromosome. If the centromere is located at a distance from the center of the chromosome, the chromosome is called acrocentric chromosome. When the centromere is present near one end of the chromosome, the chromosome is a telocentric chromosome.   

Fig. 9.5. The light micrograph on the left shows the chromosomes of late prophase as slender wavy strands. The illustration in the middle shows the general features of the metaphase chromosome. The illustration on the pattern of banding of two chromosomes, a long chromosome on the left and a short chromosome on the right. These features, namely, the length, cross banding, and position of the centriole are to classify the chromosomes by what is known chromosome typing or karyotyping. 

Karyotype

Karyotype is the individual’s complete set of chromosomes which comprises 23 chromosome pairs. Karyotyping is the study of the number and morphology of chromosomes whether normal and abnormal. Karyotyping requires microscopic examination of the chromosomes, taking  pictures and arranging them in an order from the longest to the shortest. Autosomal chromosomes are arranged in this way first followed by the two sex chromosomes put together. The  typical human karyotype consists of 22 pairs of autosomal chromosomes and one pair of sex chromosomes. Normal females contain two X-chromosomes, whereas normal males have one X chromosomes and one Y chromosome. The normal female karyotype is written as 46,XX whereas the normal male karyotype is written as 46,XY. Autosomes are numbered from 1 to 22 according to length. The sex chromosomes come at the end; the X-chromosome being longer than the Y-chromosome.

Fig. 9.6. The micrograph in black and white shows the karyotype of a male individual. The autosomes are arranged in order and numbered from 1 to 22, followed by the sex chromosomes X and Y.

Chromosomal Abnormalities 

The correct number and structure of chromosomes is an essential prerequisite for the normal functioning of cells and for normal embryonic and postembryonic development. Each chromosome contains hundreds or thousands of genes, which control all body activities.  Chromosome abnormalities are responsible for about 7% of birth defects. Moreover, about 15-20% of all pregnancies are terminated by miscarriage; about 50% of those miscarriages are caused by chromosome abnormalities that may involve an increase or decrease in chromosome number or a change in chrome structure by deletion, translocation, rig chromosome formation or other structural abnormalities.

Abnormal Chromosome Number

Abnormal chromosome number comprises and increase or decrease in the number of chromosomes; it could be an increase in the whole sets of chromosomes or an increase or decrease in the number of individual chromosomes. An increase in whole sets of chromosomes causes polyploidy, whereas the gain or loss of individual chromosomes causes aneuploidy. Excess or lack of genetic material cause health problems. Fertilization of the ovum by more than one sperm by a process called polyspermy results polyploidy. When the ovum is fertilized by two sperms the fertilized ovum will have three sets of chromosomes instead of the normal two set. This is triploidy where the ovum has a total of 69 chromosomes. Tetraploidy occurs when the ovum is fertilized by three sperms resulting in two extra sets of chromosomes giving a total of 92 chromosomes. Polyploidy is generally fatal and leads to early miscarriage, however some triploids can survive to the third trimester of pregnancy.

Fig. 9.7. The micrograph shows a triploid karyotype containing three of each type of chromosomes. This is the result of two sperms fertilizing an X-chromosome bearing ovum.

Aneuploidy denotes a total number of chromosomes that is not 46 but slightly less or more than 46 (e.g. 45 or 47). It often results from non-disjunction of sister chromatids during anaphase.  Non-disjunction is the failure of sister chromatids to separate from each other during anaphase of the cell division; this may take place during any cell division but it usually occurs during meiosis-1 or -2 of the oocyte, particularly in women over the age 35. Non-disjunction and chromosome lagging may cause trisomy, monosomy or mosaicism.

Fig. 9.8.  The illustration shows aneuploidy resulting from nondisjunction in either meiosis-1 or meiosis-2.

Trisomy is presence of three copies of the same chromosomes in cells of the body. At the time of fertilization, the ovum or sperm may contain two copies of the same chromosome. The resulting zygote will contain three copies of that chromosome, and so all cells of the body that develop from that ovum.  The total chromosome number will be 47 instead of 46. Trisomy can involve an autosome e.g., chromosomes number 13, 18 or 21 or a sex chromosome, either the X chromosome or the Y chromosome.

Fig. 9.9. The picture on the left shows features of autosomal trisomy-21 (Down syndrome) and autosomal trisomy-18 (Edwards syndrome).

Monosomy results from the loss of one copy of a chromosome resulting in a total chromosome number of 45, i.e., a 45,X or a 45,Y karyotype. Autosomal monosomy is extremely uncommon and is more serious than trisomy, often causing spontaneous abortion. Sex chromosome monosomy is usually a monosomy X (XO) that causes Turner syndrome. Turner syndrome females are often short, infantile with nonfunctioning ovaries, fallopian tubes and the uterus.

Mosaicism is the presence of different cell lines with different genotypes in the same person. It usually results from non-disjunction of autosomes or sex chromosomes during early cleavage. It could also result from anaphase lagging with the consequent loss of one chromosome. Mosaicism is less serious than monosomy and trisomy.

Fig. 9.10. The illustration shows the process of mosaicism.

Fig. 9.11. A picture (left0 and an illustration (right) show features of monosomy of sex chromosome X (Turner syndrome).

Structural chromosome abnormalities

Structural chromosome abnormalities take place during cell division as a result of chromosome breakage at fragile sites followed by loss of part of a chromosome or abnormal recombination of the chromosomes. They are of many types that include deletion, ring chromosome formation, duplication, inversion, translocation, and isochromosome formation. These will be covered in more details in the next chapters.

Deletion is the loss of  . A number of syndromes can occur as result of deletion and loss of a part of a chromosome. These syndromes are called chromosomal deletion syndromes. The effect depends on the chromosome involved, the segment which has been lost and the genes present in the lost segment. Generally, deletions tend to cause birth defects, intellectual disability, and problems with physical development. Williams syndrome is a disorder caused by deletion affecting chromosome 7, cri du chat syndrome results from deletion of a segment of chromosome 5, DiGeorge syndrome is caused by deletion of a portion of chromosome 22, whereas Prader-Willi syndrome and Angelman syndrome are caused by deletion of part of chromosome 15. The vast majority of these syndromes are characterized by intellectual disabilities. In addition, cri du chat syndrome is Characterized by a high-pitched cry that sounds like that of a cat.  Deletion may affect sex chromosomes resulting in syndromes like the fragile-X syndrome.

Fig. 9.12.  The illustration on the left shows the process of the loss of a chromosomal segment by deletion, whereas the picture on the right is a photograph of a child with the cri du chat syndrome which is caused by deletion affecting chromosome 5.

Ring chromosome formation results from loss of the ends of a chromosome by deletion followed by fusion of the ends leading to formation of a circular chromosome. It causes syndromes like ring chromosome 20 syndrome which is marked by characteristically prolonged episodes of seizure.

Fig. 9.13.  The illustration on the left shows the process of the of ring chromosome formation by deletion, whereas the picture on the right is a photograph of a child with the ring chromosome syndrome.

Isochromosome formation results from division of the centromere transversely instead of longitudinally. Accordingly, each daughter chromosome has two identical arms and is deficient in one arm. Isochromosome formation like all other structural chromosome abnormalities can affect an autosome or a sex chromosome. When it affects the X-chromosome, the affected girl will have primary amenorrhea and streak ovaries. Patients with chromosome 17 isochromosome syndrome frequently suffer from neoplasia, possibly because the tumor suppresser gene p53 is present in chromosome 17; isochromosome here may affect the gene p53. Isochromosome involving chromosome 22 may result in cat eye syndrome.   

Fig. 9.14.  The illustration on the left shows the process of isochromosome formation by transverse splitting of the centromere, whereas the picture on the right is a photograph of a child with the isochromosome syndrome showing coloboma eye.

Inversion is a rearrangement of the chromosome segments in a reverse order. It is of two types, pericentric inversion which involves both arms and paracentric inversion which involves one arm only. Affected persons are normal but their offspring may suffer abnormalities.

Duplication is the presence of an extra copy of a piece of a chromosome. There is no loss of genetic material thus it is less harmful than other structural chromosomal anomalies.

Translocation is an exchange of material between two chromosomes; it includes reciprocal translocation and Robertsonian translocation. People affected by reciprocal translocation of non-homologous chromosomes may appear normal, whereas people affected by Robertsonian translocation may suffer translocation trisomy 21 (Down syndrome).

Fig. 9.15.  The illustration on the left shows the process of chromosome segments inversion, whereas the one on the right shows the process of translocation.

Fig. 9.16.  The illustration shows the classification of chromosomal abnormalities based on number of chromosomes and chromosome structure.

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