GENETIC DISORDERS

In pathology and microbiology, characteristic features of Downs syndrome include hypotonia, mental retardation, a flat occiput, oblique palpebral fissures, epicanthic folds, flat nasal bridge, speckled irises, protruding tongue, short broad hands with curved little fingers, characteristic dermal pattern of palms, fingers, and soles, and associated cardiovascular anomalies and other congenital abnormalities. Mongoloids have a greater susceptibility to infections and an increased incidence of leukemia compared with non mongoloids of the same age group. The incidence of Downs syndrome tends to increase in relation to maternal age at time of birth. Although, in science, as already noted, this syndrome is usually associated with a trisomy 21 karyotype, in a few patients the extra chromosomal material is not arranged as a separate chromosome but is attached to another chromosome, usually number 15 so called translocation Downs syndrome as observed under the microscopes. This type of mongolism apparently is not related to maternal age. It may be filial but frequently arisen de novo. In microscopy, patients with translocation Downs syndrome have 46 chromosomes, including the translocation chromosome, and clinical features similar to those with the usual trisomy 21 as seen through microscopy. In another small group of mongoloids, chromosomal analysis reveals cells of two different genotypes, mosaicism in the same patient, 47 chromosomes with trisomy 21 in some cells and a normal number of chromosomes, which are 46 in other cells as examined using the microscopes. In these patients, the clinical features may differ from those of the usual Downs syndrome. For example, external mongoloid features may be present, but the patient may have a normal mentality.

Trisomy E and D

Other congenital abnormalities with trisomy of autosomal chromosomes have been described such as trisomy of a chromosome of the E group, most likely number 18, and trisomy of one of the D group of chromosomes. External and internal abnormalities are seen characteristically in the E and D trisomies, and death usually occurs early in life. The E18 trisomy, for example, is characterized by a prominent occiput, micrognathia, low set eyes and ears is generally believed that a correlation exists between XYY and criminal or antisocial impulses, some investigators with the help of microscopy and microbiology urge caution in accepting the interpretation that there is a specific association of XYY with criminal behavior.

Aberrations in Structure

As seen in microscopy, pathology and microbiology, certain genetic disorders are characterized by structural aberrations of the chromosomes such as deletion, which indicates a loss of a portion of a chromosome, when both terminal portions are lost, the broken ends may unite to form a ring chromosome, duplication, which is the presence of an extra piece of a chromosome inversion, the fragmentation of a chromosome, followed by a rejoining of the fragments in such a way that they are inverted or reversed with respect to the rest of the chromosome, translocation, which is the transfer of a portion of one chromosome to the abnormal chromosomes resulting from division of the centromere perpendicularly to the long axis of a chromosome, rather than parallel to it.

An example of deletion involving the short arm of a chromosome of the B group is observed in the cri du chat syndrome, so called because the affected cry of the infant resembles the meowing of a cat. In pathology, microcephaly, mental retardation, hypertelorism, prominent epicanthal folds, and low set ears commonly occur in these patients. The catlike cry and the prominent epicanthal folds disappear with aging. Other deletion syndromes in pathology associated with microcephaly, mental retardation, hypertelorism, and a variety of malformations have been described, involving chromosomes number 4 and number 18 and one of the D group, 13 to 15, forming a ring chromosome. In microscopy, the Philadelphia chromosome observed in the leukocytes of patients with chronic granulocytic leukemia, an abbreviated 21 autosome with its long arms substantially shortened, is another example of deletion. Recently, it has been observed and shown through the microscopes that the material from this chromosome may be translocated to one of the number 9 chromosomes. In the forms of acute leukemia, aneuploidy, which is an abnormal number of chromosomes, has been demonstrated in bone marrow cells, particularly when prepared by the direct fixation technique. In pathology and microbiology, chromosomal abnormalities, such as breakage with translocation or deletions, including an anomaly similar to the Philadelphia chromosome of leukemia, have been observed in patients who have been using lysergic acid diethylamide or LSD, but in the published reports, there is no general agreement among investigators that LSD or other hallucinogens cause chromosomal damage. Chromosomal aberrations as seen under the microscopes have been detected in cells of neoplasms other than leukemia, as well as in cells of tissues exposed to ionizing radiation. Recent improvements as examined under the microscopes in cell culture techniques have permitted not only the identification of chromosomal anomalies but also the diagnosis of inborn errors of metabolism and the detection of heterozygous carriers of these disorders. The detection of enzymes in cells cultured from amniotic fluid obtained by amniocentesis has been helpful in establishing the prenatal diagnosis of certain familial metabolic disorders.

INHERITANCE PATTERNS

In pathology and microbiology, the inherited disorders resulting from mutant genes are known as autosomal or sex linked, depending upon whether the affected genes are in the autosomes or in the sex chromosomes. A dominant disease in pathology is one that is clinically manifest in an individual who has only one mutant gene or in a heterozygous state. A person with two abnormal dominant genes or in a homozygous state would be phenotypically similar to the heterozygote. In pathology, however, since diseases related to dominant genes are so uncommon, it is extremely unlikely in practice to encounter such a homozygous individual, because the latter can result only from mating of two affected persons. A recessive disease is one that is apparent only in a homozygous subject. It is not evident in a heterozygote, but the latter is a carrier of the condition.

The patterns of hereditary transmission in pathology are classified according to the classic Mendelian categories. A variety of patterns of inheritance have been observed some simple, others complex. Those readily recognized are the simple patterns produced by rare genes at a single locus that include autosomal dominant, autosomal recessive, sex linked dominant, and sex linked recessive as seen using the various microscopes such as light microscopes, forensic microscopes and electron microscopes. In almost all of the sex linked disorders, the mutant gene is on the X chromosome, and this is the entity referred to when the term sex linked is used without qualification. Well substantiated examples of Y linked traits are rare, occurring only in males as observed under the microscopes.