How CAH Genes Translate Into Symptoms: The Genotype/Phenotype Connection
By Erin Anthony
Congenital adrenal hyperplasia is a fairly well characterized disorder, but its effects are far from simple. CAH is caused by mutated recessive genes and the physical effects can range from severe cases evident at birth to those that are never diagnosed. Even within the same family, the characteristics of CAH can be markedly different.
Understanding the different ways in which CAH can occur requires understanding the difference between phenotype and genotype—between what you see and what you get. In other words, phenotype refers to observable physical characteristics, while genotype refers to the genes a person carries within their body’s cells.
The Basics
Humans are “diploid,” having two copies of every chromosome—one from their mother and one from their father—46 in all. Within each chromosome are genes, the body’s directions for operation. Because every person has two copies of each chromosome, they also have two copies of each gene.
A gene can be dominant or recessive. As you might expect, a dominant gene takes precedence over a recessive gene. In fact, recessive genes only get the opportunity to show themselves when there are two copies of them (double recessive genes) for a given trait.
For each gene there are variations, or alleles. Some genes may have only one or two variations, while others, like those responsible for CAH, may have several variations.
A person’s genetic combination is called their “genotype.” Sometimes genes acquire glitches or mutations. And, while the body is usually pretty good about fixing these problems, a few persist and are passed down from generation to generation—such as with CAH.
Which alleles a person receives depends on the combination of parental gametes (eggs or sperm). Depending on which alleles a person receives, their genotype (and as a result, their phenotype) will be different.
The phenotype is the physical expression of the genotype. Blue eyes, a birthmark and CAH are all examples of phenotypes. Depending on the combination of alleles, whether they are dominant or recessive, as well as other complicating factors, phenotypes will vary.
Genotypes and Phenotypes of CAH
CAH is a recessive disorder that results in the deficiency of one of five enzymes required for the production of cortisol. Because it’s recessive, a person with CAH (having the phenotype) must have two mutated copies of the gene, one from each parent.
The most common cause of CAH is mutation of the gene CYP21A2, which causes deficiency of the enzyme 21-hydroxylase. According to researchers, CYP21A2 is one of the most polymorphic (“many-formed”) human genes studied to date. This means it has many different variations, or alleles.
CYP21A2 is found on the short arm of chromosome 6, in a region that also carries many other important genes whose products control immune function. Mutations of CYP21A2 affect males and females equally and has been found at a frequency of 1 in 60 in the general population—meaning in a group of 60 people, one will carry a mutation of CYP21A2 on one of their chromosomes. A few different terms are used to describe different genotypes. For CAH, the terms refer to the presence of mutations. People with two copies of the same mutation are called “homozygous” while people with two different kinds of mutations are “compound heterozygous.” A person with only one mutant copy of a gene is “heterozygous,” or a “carrier,” and has no symptoms of the disorder.
Knowing a person’s genotype allows physicians and genetic counselors to calculate the probability of a child inheriting a particular trait. In this case, knowing the genotype and predicting the phenotype may influence prenatal care.
For two carriers of a CYP21A2 mutation, there is a 25 percent chance they will have a child with CAH. A child born to a carrier and non-carrier would have a 50 percent chance of also being a carrier. Two affected individuals have a 100 percent chance of having a child with CAH.
Although genotypes are easily predicted, the resulting phenotypes are not as simple. Because CYP21A2 has so many different variations, there are several different mutations that can occur. Here, only the most common mutations—associated with 21-hydroxylase deficiency—will be discussed.
CAH phenotypes (classic salt-wasting, simple virilizing, and non-classical) depend on the severity of the mutations. The type of mutation determines the level of enzymatic activity (or inactivity). Enzymes are produced according to what the gene “says”—so if a gene is defective the resulting enzyme will also be defective.
For CAH, the phenotype is usually the result of the less severely affected allele. CYP21A2 mutations can be grouped into three categories according to how enzymatic activity is affected.
The first group is most often associated with salt-wasting CAH. It consists of severe mutations such as deletions (loss of all or parts of the gene’s information) or nonsense mutations (changes that “don’t make sense” to the molecules that “read” the gene) that completely stop enzyme activity needed to make cortisol and aldosterone.
The second group is usually associated with the simple virilizing form of CAH. It consists mostly of “mis-sense” mutations, where the enzyme-making instructions are changed but the enzyme still has some function. Here, the enzymes usually have 1 to 2 percent of their normal activity and so permit the body to make aldosterone, the main sodium-retaining hormone made by the adrenal glands.
The third group of mutations is usually associated with nonclassical CAH (NCAH). It consists of mutations that produce enzymes retaining 20 to 60 percent of their normal activity—so the resulting phenotype is usually less severe and usually detected later in life.
It is important to note that dividing phenotypes into distinct groups is a simplification. In reality, there may be a continuum of phenotypes even within the same genotype. Humans are highly dynamic and unique in the expressions of their genes. Thus, the rest of a patient’s genetic background will influence their CAH phenotype. Modifying genes, such as those that regulate the production of androgens and estrogens, as well as individual sensitivity to these compounds, will influence a patient’s phenotype.
A French study of women with NCAH emphasizes the complicated genotype-phenotype relationship. Studying the genotype-phenotype correlation in women with NCAH is important because those carrying a severe mutation of CYP21A2 risk giving birth to children with the classical form of the disease. Here, screening for carrier status in the partner is crucial.
Deneux, et al., reported in The Journal of Endocrinology and Metabolism in 2001 that phenotype cannot always be predicted by genotype and in some cases may be milder than expected.
According to Deneux, 2 subjects in the study were found to carry 2 potentially severe mutations often associated with the simple virilizing form of the disorder, but showed no virilization at birth. The clinical and biological phenotypes of the patients were particularly marked and may indicate a phenotypic continuum among the three forms of 21-hydroxlyase deficiency, the researchers said.
According to Deneux et al., “This failure of strict correspondence of phenotype and genotype must be borne in mind when performing a prenatal fetal DNA analysis. Predicting phenotype must remain cautious.”
The complicated relationship between genotype and phenotype in patients is highlighted in families with both symptomatic and asymptomatic forms of NCAH. According to Deneux, et al., this confirms that variability in phenotypic expression is influenced by factors other than heterogeneity of CYP21A2, such as modifying genes, individual differences in adrenal and extra-adrenal chemical pathways, cortisol requirements, and individual sensitivity to androgen oversecretion.
Understanding the relationship between genotypes and phenotypes for CAH is important for better management of the disorder. When physicians and genetic counselors know more about the relationship between genotypes and phenotypes, quality of life for patients improves.
The author, a CARES member, is a senior at Lehigh University, majoring in biology and science / environmental writing.
