Occurring in about 1 in 300 children, hypertrophic pyloric stenosis (HPS) is five times more likely to occur in males than in females. When a child with HPS is born, the recurrence risk in future progeny is 5% to 10% for males and 1.5% to 2% for females. In adulthood, the risk of an affected male having an affected child is markedly increased over the general population: 4% of sons and 1% of daughters of such men would be likely to be affected. Even more striking is the risk to children born to affected females: 17% to 20% of sons and 7% of daughters are affected.
The thickness of the pyloric muscle may be distributed across a bell-shaped curve; the position on the bell-shaped curve is determined by many factors, including the expression of multiple, unknown genes. HPS may result when an individual’s genetic and environmental influences cause him or her to fall to an extreme position on this curve, past a certain point, which is called a threshold. In HPS, this threshold is farther to the left for males than it is for females.
Before 1998, myelomeningocele affected 1 in 1000 liveborninfants in the United States. Anencephaly occurred with a similar frequency, although most infants were either stillborn or diedin the neonatal period. Since 1998, because of the supplementation of food staples with folic acid, both of these conditions havebecome far less frequent. Multiple genetic and nongenetic factorsdictate the speed with which the neural tube closes, as follows: 1.
The frequency of neural tube defects (NTDs) varies greatly in different ethnic groups. NTDs are more common in the British Isles, where, in 1990, they occurred in 1 in 250 live births, and far less common in Asia, where the frequency was 1 in 4000. These ethnic differences suggest a genetic component.
2.
Couples from the British Isles who move to the United States have a risk intermediate between the risks in the United Kingdom and the United States, suggesting an environmental component.
3.
The occurrence of NTDs exhibits seasonality. In the United States, affected infants are more likely to be born during late fall and early winter, again suggesting an environmental component.
4.
Periconceptual supplementation with folic acid has significantly lowered the risk of having an infant with an NTD. This nutritional influence suggests an environmental component.
5.
Parents who have one child with an NTD are 20 to 40 times more likely to have a second affected child; this provides further evidence of a genetic component.
Disorders with Unusual Patterns of Inheritance
Human cells contain non-nuclear DNA; a single chromosome is present in each mitochondrion, and mutations within this DNA are associated with a group of diseases.
Mitochondrial DNA (mtDNA), which is circular and 16.5 kb in length, replicates independently of nuclear DNA. Involved in energy production used to run the cell, mtDNA codes for a few respiratory chain proteins (most mitochondrial proteins are coded on nuclear DNA) and for a set of transfer RNAs unique to mitochondrial protein synthesis. Virtually all mitochondria are supplied by the oocyte, which means that mtDNA is maternally derived. A woman with a mutation in mtDNA passes this mutation to all of her children. More than one population of mitochondria may be present in the oocyte, a phenomenon called heteroplasmy. The mtDNA mutation may be present in a few or many mitochondria. When the fertilized egg divides, mitochondria are distributed randomly. The presence of symptoms in the offspring, and their severity, depends on the ratio of mutant to wild-type mtDNA present in a particular tissue. If an abundance of mutant mitochondria exists in tissue that has high energy requirements (brain, muscle, and liver), clinical symptoms occur. If fewer mutant mitochondria are present, few clinical symptoms may be seen.