Deformities

Congenital disorders known as deformities are defined as a secondary bending or change of shape. Commonly, these involve a lack of amniotic fluid (oligohydramnios) buffering the fetus from the pressure of the uterine wall and may be due to leakage or failure to produce fluid. Characteristics include flattening of the nose and ears, fixation of the joints (leading to clubbed hands and feet), growth retardation, and underdevelopment of lungs and gut. Arthrogryposes (clawed fingers and contracted joints) may be caused by extrinsic pressure, resulting in joint or limb deformities; however, the majority of cases are caused by intrinsic problems such as weakness from congenital spinal cord, nerve, or muscle dysfunction or abnormal formation of joints. Many intrinsic arthrogryposes are genetic disorders.

Metabolic disorders

A large class of congenital disorders includes inborn errors of metabolism. The causes are hereditary and usually biparental, but they may occasionally be due to mutations on the X-chromosome or in the mitochondrial DNA. Mitochondrial DNA and diseases due to mitochondrial mutations are inherited in a strictly matrilineal manner. The mother’s generally normal metabolism could, via the placenta, compensate for her infant’s impaired metabolism, in which case no prenatal effects would be expected in the infant at birth. This is true in many metabolic diseases involving relatively small molecules such as amino acids, simple sugars, and some hormones. In these conditions, separation of mother and fetus at birth heralds the onset of symptoms. The biochemical aspects of human metabolic diseases are enormously complex and rely heavily on modern technical and chemical advances for detection. See metabolic disease.

Blood disorders

Congenital metabolic defects of pigments (porphyrins) derived from the oxygen-carrying molecule hemoglobin in red blood cells may occur. Faulty or deficient production of hemoglobin leads to anemia or red blood cell defects categorized as sickle-cell disease and thalassemias. Congenital bleeding disorders may involve blood vessels, connective tissues, or clotting factors. The best known is hemophilia, caused by mutations of an X-linked gene.

Other congenital disorders

The most common congenital disorder affecting cell membrane transport is cystic fibrosis. In the United States, the condition occurs in 1 in every 2,500 births, meaning that 4 percent of all persons are carriers of cystic fibrosis. Of the muscular dystrophies, the X-linked form named for French neurologist Guillaume Duchenne (1806–75) is the most common, and, despite detailed knowledge of the causative gene and its effect, it remains a lethal condition. The best known of the many congenital disorders of connective tissue is Marfan syndrome, a rare cause of sudden death in young athletes. The rare class of genetic disorders called imprinting defects is due to abnormal parental expression of usually normal genes. Imprinting defects result in improper embryonic and fetal growth and metabolism and placental function. Less commonly, these genes are deleted or mutated.

There are numerous congenital immunodeficiency syndromes, some of which may not become manifest until exposure to a specific group of infectious organisms occurs. Another large group of congenitally caused disorders involves hormone deficiency or insensitivity, such as lack of growth hormone production or resistance of receptors to estrogen or testosterone.

Causes

Most congenital disorders, especially malformations, occur sporadically, as a single isolated case within a family. The same sporadic occurrence in hereditary disease is either because family size is too small or because the disorder represents a new mutation, occurring for the first time in the male or female germ cell and leading to the conception of the affected child. Most chromosome abnormalities represent sporadic occurrence, and in cases of trisomy of chromosomes 13, 18, or 21, there exists a strong correlation with advancing maternal age. Many inborn errors of metabolism are the result of mutations inherited in maternal mitochondrial DNA. Parental defects in the regulation of gene expression cause genomic imprinting defects that result in abnormal expression of maternal and paternal alleles and disruption of embryonic development. In autosomal recessive disorders—that is, disorders inherited from both parents—each parent carries one mutated copy (allele) of the given gene. The same chance of disorder applies at each conception regardless of the outcome of preceding pregnancies. Environmentally caused disorders such as fetal alcohol syndrome are presumably preventable.