Genetic

Congenital malformations:

This topic is discussed within the context of genetic diseases because it has some bearings to those diseases. Not all congenital malformations, as it may come to the mind of the student, are caused by genetic aetiology; but only a small percent of them are so. The majorities of congenital malformations are caused by environmental aetiology, and from this angle comes their relationship to genetic diseases.
If congenital malformations are represented by a big circle (that encompasses genetic disease in addition to others) Figure (1), the largest group i.e. 2/3 of the surface area is of unknown aetiology, while only a small sector represents diseases of genetic basis.

Definition:

It is a deformation of structure or function of an organ present at birth.
It may be on the surface of the body, e.g. cleft lip or inside the body, e.g. horseshoe kidney; it may be macrocellular, i.e. recognized by the naked eye e.g. club foot or microcellular i.e. recognized only by microscopical examination, e.g. sponge kidney where the defect is abnormal connection between the collecting tubules and the urineferous tubules leading to thin microscopical dilatation that gives the kidney a spongy feeling; it could be diagnosed by mere naked eye, e.g. microcephaly HYPERLINK "Photo%20genetics/Microcephaly.ppt" [] or microphthalmia HYPERLINK "Photo%20genetics/Microphthalmia.ppt" [] or it may need special procedure for diagnosis, e.g. congenital heart defects; it may present at birth showing signs and symptoms, e.g. tracheo-esophageal fistula or the signs and symptoms may present later in life (but the defect is actually present at birth), e.g. adult polycystic kidney; it may be familial or non-familial, i.e. either there are multiple cases in one family or it is the only case in the family (sporadic); and lastly it could be genetic, i.e. direct descent from parents through genetic defect or could be non-genetic, i.e. caused by environmental causes, e.g. microcephaly; some cases are genetic while others are due to uterine infection during pregnancy (prenatal infection).
Causes
The etiological factor that results in congenital malformation is known as a teratogen. Some teratogens may act as mutagen or carcinogen.
The effect of a teratogen is most effective on growing tissue with rapid division rate but not all teratogens affecting different foeti cause the same severity of action, i.e. the action of one teratogen is variable in different foeti. This is due to the following factors
Dose of the teratogen: larger doses of course causes severer effects.
Time of exposure to the teratogen, e.g. the action of the Mullerian inhibiting factor (MIF) which is an enzyme produced by the foetal testis at a certain time (7th week post-fertilization) to effect the regression of the female primitive reproductive organ in a male foetus. If the testis fails to produce this enzyme at that time, then it will have no effect and the female reproductive organs will remain inside the abdomen of the male infant resulting in ambiguous genitalia.
Host susceptibility: some foeti are more susceptible than others for the same dose and therefore they are more severely affected.
Interaction with other factors, environmental or genetic constitution of the foetus.

Types of teratogens

I. Genetic, these could be:
Single gene that is either:
autosomal dominant (AD).
autosomal recessive (AR).
sex-linked dominant (XD).
sex-linked recessive (XR).
Chromosomal abnormality that could be:
numerical.
structural.
II. Environmental teratogens; these causes:
In-utero infection :
Prenatal infection of the fetus with bacteria, viruses, or parasites may occur during pregnancy due to maternal infection that is transferred to the fetus through the placenta causing fetal infection. The most common is the viral infection with rubella virus (German measles), and influenza virus.
Rubella usually causes severe malformation the earlier it infects the fetus The modern immunization against rubella of girls at reproductive age is one of the very successful methods to prevent this type of malformation.
Usually, rubella causes congenital heart defect, mainly septal defects, microcephaly, cataract [], or infection of the chambers of the eyes leading to blindness, deafness and mental retardation.


Influenza virus usually causes cleft lip and palate HYPERLINK "Photo%20genetics/Cleft%20Lip%20And%20Palate.ppt" [] and neural tube defects

Toxoplasmosis is a parasite infestation contracted from animals, usually sheep or cats; it may cause microcephaly, jaundice, and mental retardation.

Physical teratogens :

These could be in the form of:
Heat, whether sauna bathing, or from weather or fever (if it does not cause abortion) usually causes neurological abnormalities and neural tube defects.
Physical pressure that may be caused from inside the uterus or outside it, pressing the growing foetus and thus preventing its proper growth.as uterine fibroid.
Ionizing radiation, whether diagnostic or therapeutic. Radiation or accidents usually causes malformation. Radiation causes microcephaly, anophthalmia and spina bifida. The most sensitive period for the foetus is the 1st two weeks post-fertilization to the 4th-5th weeks of conception.
Chemical teratogens, these could be :
Non-medicinal: like insecticide, and household chemical used in cleaning and industrial chemical. Some of those usually contain organic phosphorous, which is very toxic. These usually are ingested accidentally to contaminate food and water, also alcohol and cigarette smoking in this category, both cause intrauterine growth retardation and also delayed mental development in later life after birth with small stature.
Medicinal chemicals : one should consider that any drug is not safe during the early weeks post-fertilization and medication should be taken cautiously of the most properly documented drug in causing congenital malformation is:
Thalidomide: a drug used for sedation of hyperemesis gravidarum, usually caused amelia and phocomelia

Anti-convulsant, Anticoagulant, Cytotoxic drugs and hormones: like progesterone, estrogen and cortisone.
Maternal disorders
Diabetes, whether treated or not. Cause macrosomia of fetus

Maternal phenylketonuria (PKU), which is a genetic disease that could be treated. Females may reach reproduction with normal state but their high phenylalanine that results from their deficiency of phenylalanine hydroxylase enzyme will destroy the developing brain to cause mental retardation in the fetus.
Thyroid: maternal hypothyroidism will cause a high degree of thyroid stimulating hormone that will suppress the fetal thyroid gland resulting in a state of hypothyroidism after a short period of hyperstimulation (cretinism).