Course:MEDG550/Student Activities/Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia

Overview

This image shows the location of the adrenal glands within the body.

Congenital adrenal hyperplasia (CAH) is a genetic condition that affects the adrenal glands. The adrenal gland sits right above each kidney. They make hormones (chemical messengers) that control processes like stress levels, blood pressure, metabolism, and sexual development. In more than 90% of people with CAH, a specific enzyme (protein that causes chemical changes in the body) does not work properly. This enzyme is called 21-hydroxylase and is found in the adrenal glands. This page will cover information specifically about CAH caused by the 21-hydroxylase either being missing or not working properly (21-hydroxylase deficient CAH).

Medical

There are three important hormones made in the adrenal glands:

• Cortisol: involved in maintaining blood sugar levels, protecting the body from stress, and stopping inflammation
• Aldosterone: controls how much salt is kept within the kidneys. This affects blood pressure levels.
• Androgens: produces male hormones, which are there in both males and females

When 21-hydroxylase is not present or not working properly, substances that are used to form cortisol and aldosterone build up in the adrenal glands and get converted into androgens. Making too many androgens causes abnormalities in sexual development. When enough cortisol is not made, it causes the adrenal glands to work extra hard and induces hyperplasia (too much growth). The adrenal glands are hyperplastic at birth, which is why it is called ‘congenital’ adrenal hyperplasia.

Types of CAH

There is a classic and non-classic form of CAH.

Classic

This form of CAH occurs in about 1 in 15,000 newborns. It is further divided into two categories: salt-wasting and simple virilizing.

Salt-wasting

This is the most severe form of CAH. The adrenal glands cannot make aldosterone, which causes the individual to lose too much salt through their pee. If too much salt is lost, it can be life-threatening in early infancy. This is the most severe type of CAH. About 75% of people with CAH have the salt-wasting type. Hormone production is very low. Babies with this type of CAH can have poor feeding, weight loss, dehydration, and vomiting.

This image shows an example of ambiguous genitalia in females.

Simple virilizing

This is a less severe form of CAH compared to the salt-wasting type. These individuals do not lose salt.

In both types of classic CAH, females have external sex organs that look different (called “ambiguous genitalia”). Males have typical male sexual organs but the testes may be smaller than usual.

Non-classic

This form of CAH occurs in about 1 in 1000 individuals.

This is a milder form of CAH compared to classic CAH. Females with the non-classic form have genitalia that is typical for females. As affected females get older, they could experience reduced fertility, irregular periods, and hirsutism (more hair in areas where it is normally not present or very little). Males with non-classic CAH may have early beard growth and small testes. Some individuals do not have any symptoms of the condition.

Genetics

Genes give our bodies instructions on how to grow and develop. 21-hydroxylase deficient CAH is caused by mutations (harmful gene changes) in the CYP21A2 gene. This gene provides the body with instructions on how to make the 21-hydroxylase enzyme. How severe the condition is depends on how much 21-hydroxylase enzyme is there and how well it works.

Individuals with the classic form of CAH have a normal amount of enzymes but there are problems with how well they work. In the salt-wasting form of CAH, these individuals have genetic changes in the CYP21A2 gene that result in this enzyme not working at all. People with the simple-virilizing form of this condition have CYP21A2 gene changes that allow for the enzyme to function at low levels. Individuals with the non-classic form of CAH have CYP21A2 gene changes that cause there to be a lower amount of enzymes than normal.

This image shows the autosomal recessive inheritance pattern, which is how CAH is passed down in families when both parents are carriers.

Inheritance

We each get one copy of our genes from our mothers and one copy from our fathers. In other words, we have two copies of all our genes. CAH gets passed down in families through an autosomal recessive inheritance pattern. ‘Autosomal’ means that the condition can affect males and females equally. ‘Recessive’ means that a person must have mutations in both copies of the CYP21A2 gene to develop the condition. People who only have mutations in one copy of the gene are called “carriers”. These people do not have symptoms of CAH.

Carriers of CAH each have a 50% chance of passing on the mutated CYP21A2 gene copy to each child and a 50% chance of passing the normal copy of CYP21A2 to each child.

If two carriers of CAH have a child, for each new baby, there is:

• A 25% chance that the child will inherit two mutated copies of the CYP21A2 gene. If both these copies are inherited, they will have CAH.
• A 50% chance that the child will be a carrier like their parents. They will not have CAH.
• A 25% chance that the child will get two working copies of the CYP21A2 gene. They will not have CAH.

If a carrier has a child with a non-carrier (i.e., someone with two normal copies of the CYP21A2 gene), the child will not have CAH. However, there is a 50% chance that the child could be a carrier like their parent.

While a child who is a carrier will not have symptoms of CAH, it can affect family planning if the child’s partner also happens to be a carrier.

Diagnosis

Some forms of CAH can be diagnosed at birth. Milder forms of CAH may not be diagnosed until childhood or adulthood. Newborn screening is often able to detect CAH.

A newborn may also look normal at first, but within a few days, may not eat properly. They may also become dehydrated and sick. This can prompt more investigation.

Diagnosis as an infant or later in life may include:

• a physical examination to look for ambiguous external genitalia in females. We usually find that the internal sex organs like the uterus and ovaries are normal.
• taking a family history to identify any diagnoses of CAH or symptoms associated with the condition

• an ultrasound of the adrenal glands can also be done to observe whether they are hyperplastic
• a blood test to determine hormone levels produced by the adrenal glands
• a genetic test for mutations in both copies of the CYP21A2 gene

Management and prognosis

Management mainly includes hormone supplementation and potentially reconstructive surgery. Hormone supplementation can be used to optimize growth. Particularly in women, it can be used to suppress androgens and promote fertility. Specific recommendations can be made by a doctor depending on how severe the CAH is.

Classic CAH

People with classic CAH are given medications called glucocorticoids. These replace the cortisol their body can’t make. More glucocorticoids may be needed when sick with an infection.

Individuals with the salt-wasting form of CAH also need medications called mineralocorticoids. These are needed to replace the aldosterone that their bodies cannot make. Newborns might need salt supplements. Surgery can correct ambiguous genitalia in females, but parents may choose to wait until the child is old enough to be a part of making that choice.

Nonclassic CAH

Some people with nonclassic CAH do not have symptoms and do not need treatment. Other people might need glucocorticoids in small doses because it might help with fertility. However, they might not need treatment throughout life.

Prognosis

Children generally grow faster than normal in early childhood, but their final height is usually shorter than expected. However, they can grow and develop normally if the missing hormones are replaced with the correct amount. Their lifespan can also be normal.

Genetic Counselling

Speaking with a genetic counsellor can be helpful to better understand the information presented in this section. They will be able to guide you on carrier testing, the pros and cons of different testing options during pregnancy, and to discuss any psychosocial concerns related to CAH.

Carrier testing

If specific mutations in the CYP21A2 gene are known within the family, family members can be tested to see if they are carriers. If a person who carries the genetic change for CAH wants to have a baby, their partner can have carrier testing to determine the chance of having a baby with CAH.

This is an image of how an amniocentesis is done.

Prenatal testing options

If the genetic changes causing CAH in the family are known, the baby can be tested during pregnancy to determine if CAH is present. The testing can be performed by the following procedures:

• Chorionic villus sampling (CVS): A sample of the cells from the placenta are taken through either the belly or cervix between 11-13 weeks in pregnancy. The genetic material of the placenta is usually the same as the baby.
• Amniocentesis: There is fluid surrounding the baby during pregnancy. It is called amniotic fluid. It contains some of the baby’s cells. A sample of this fluid can be taken after 15 weeks in pregnancy.

Both the CVS and amniocentesis samples can be used for genetic testing to find out if the baby has harmful mutations in both copies of the CYP21A2 gene.There is a small risk of losing the baby with CVS (1% risk) and amniocentesis (0.5% risk). However, it can tell you for sure if the baby has CAH.

Preimplantation genetic diagnosis

To select for a child without CAH, there is the option to produce an embryo through in vitro fertilization (IVF) and test the embryo for CAH. This can be done when mutations in the family causing CAH are known. Cost is an important factor to consider when thinking about this option.

Other considerations

Research suggests that some women experience concerns related to romantic partnerships, greater pain during sexual intercourse, and lower body confidence. Both men and women may experience anxiety, lower self-esteem, and concerns regarding their identity. However, every person with CAH can have different psychosocial experiences in response to having the condition.

People diagnosed with CAH should have a health care team that includes at least an endocrinologist, genetics provider, and mental health worker.

Additional Resources

CARES Foundation: https://caresfoundation.org/

Living with CAH: https://www.livingwithcah.com/

Find an endocrinologist: https://www.endocrine.org/patient-engagement/find-an-endocrinologist-directory