What is 17-Hydroxylase Deficiency?
Congenital adrenal hyperplasia (CAH) is a group of genetic conditions that happen when there is a lack of a specific enzyme needed to produce certain key hormones in the adrenal glands. These glands are found above the kidneys and are responsible for releasing essential hormones. The hormones typically affected are cortisol, aldosterone, or both. The most common cause of CAH is a mutation or deletion of a gene called CYP21A, causing a condition known as 21-hydroxylase deficiency. This specific defect is behind more than 90% of all CAH cases. Conversely, a condition known as 17-hydroxylase deficiency is a rare cause of CAH, making up just about 1% of cases.
The specific type of CAH that someone has depends on several factors including the person’s sex, the specific type of deficiency they have, and how severe the gene mutation or deletion is. Unlike the more common 21-hydroxylase deficiency, the 17-hydroxylase deficiency may not be detected at birth. Instead, it is often discovered later, when signs such as unclear sex characteristics, late start of puberty, high blood pressure, or low potassium levels are noted. Typically, 17-hydroxylase deficiency shows as sexual nondevelopment in females with two X chromosomes and ambiguous sex characteristics in males with an XY chromosome configuration.
This article will concentrate on the causes, frequency, and characteristics of this rare genetic disorder. We will also discuss the importance of medical professionals working as a team for early detection and management of this condition.
What Causes 17-Hydroxylase Deficiency?
Congenital adrenal hyperplasia, or CAH, is a genetic disorder that is received from both parents. It occurs when specific enzymes in the body aren’t present in the right amounts. One rare cause of CAH is a deficiency in the enzyme known as 17-hydroxylase. This deficiency is due to changes in the genetic material in the CYP17A1 gene found on a particular area of chromosome 10.
The deficiency results in the loss of function of not just one but two important activities in the body – 17-hydroxylase and 17,20-lyase. Both activities play a significant role in the production of cortisol (a hormone that helps the body respond to stress) and sex hormones. Specifically, 17-hydroxylase helps to produce three essential substances: 17-hydroxypregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone (DHEA). The production of DHEA, which is a precursor to sex hormones, is particularly crucial.
At this time, over 100 changes in the CYP17A1 gene are known to contribute to the disorder. Most of these changes result in a complete loss of both 17-hydroxylase and 17,20-lyase functions. However, cases where only some enzymatic activity is lost, or just one of the two activities is lost, have also been observed. Some patients have different changes in each copy of their CYP17A1 gene. This variety of gene changes can lead to different levels of disease severity, even in individuals with the same mutation. To identify known mutations in the CYP17 gene, molecular genetic testing is available.
Risk Factors and Frequency for 17-Hydroxylase Deficiency
Congenital adrenal hyperplasia due to 17-hydroxylase deficiency is a rare condition, making up only 1% of cases globally. While we’re not sure exactly how common it is, we believe it occurs in about 1 in 50,000 people. The condition is more prevalent in countries like Brazil, China, and Japan, where it’s the second most common cause of congenital adrenal hyperplasia. We think this higher rate is because of the founder effect – where a small group of people start a new population – but we need to do more research to know how common the mutations causing this condition are in all populations.
Signs and Symptoms of 17-Hydroxylase Deficiency
Patients with 17-hydroxylase deficiency do not show the same signs as those with classical CAH (Congenital Adrenal Hyperplasia) due to 21-hydroxylase deficiency; hence, they are often diagnosed later in life. Instead of having an adrenal crisis, these patients might experience high blood pressure and low potassium levels in their childhood or adulthood. This happens because of an excess of a hormone called aldosterone which is stimulated by excessive amounts of another hormone, ACTH. The other symptoms they develop relate to a lack of sex hormones and usually become noticeable during puberty. The symptoms depend on the patient’s genetic sex.
- 46XX Patients (genetically female):
If these patients do not experience high blood pressure or low potassium levels before puberty, they typically won’t have any symptoms or physical changes until puberty age. At that time, they may start to notice that puberty is delayed, they have not started their periods, and they are not developing as other girls of the same age (lack of secondary sexual characteristics). When examined, they will have female genitalia, a uterus that has not matured, and potentially cystic ovaries, but all these are expected before the start of puberty.
- 46XY Patients (genetically male):
These patients usually have underdeveloped male features that can range from appearing completely female to having inconspicuous or small male genitalia.
- Phenotypic female 46XY patients: These patients might have a history of abdominal hernia or a lump in the groin due to testes that haven’t descended. If not detected until puberty, they will have similar symptoms to 46XX patients: delayed puberty, no periods, and lack of secondary sexual characteristics. In terms of physical examination, they will lack a proper vagina and lack internal female genitalia which is judged by the presence of a blind pouch instead. The testes may be undescended or found in the groin area when imaging studies are performed.
- Males with ambiguous or small male genitalia: These patients may have undescended testes or other issues associated with lack of male characteristics at puberty. Some have also reported having excessive breast tissue.
Testing for 17-Hydroxylase Deficiency
If doctors suspect you are experiencing 17-hydroxylase deficiency, several tests may be administered to confirm the condition:
* The levels of Adrenocorticotropic hormone (ACTH), a hormone that regulates the body’s response to physical stress, might be checked. A high ACTH level could indicate this issue.
* In patients who have gone through puberty, the levels of Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) – these are hormones that regulate the reproductive system – could be elevated.
* They may perform an ACTH stimulation test. This includes checking the levels of several hormones like 17-hydroxyprogesterone, cortisol, deoxycorticosterone, 17-hydroxypregnenolone, dehydroepiandrosterone, and androstenedione to assess your adrenal gland function and to pinpoint where the hormone production might be going wrong.
* Levels of aldosterone and plasma renin, hormones that help control blood pressure, could be checked. However, these levels can fluctuate among different individuals.
* A basic metabolic panel may be taken to check for low levels of potassium in your blood (hypokalemia) and metabolic alkalosis, a type of electrolyte imbalance.
* For patients who physically appear to be female (phenotypic), a karyotype – a test that provides a picture of a person’s chromosomes – might help to determine their genetic sex.
* Genetic testing could identify specific gene mutations that can cause this condition.
In the case of patients who physically appear to be female, an imaging test like a pelvic ultrasound might be carried out. This test helps to determine if the patient has female reproductive organs, or potentially undescended testes in the case of patients who are genetically male.
Treatment Options for 17-Hydroxylase Deficiency
Medical treatment for a congenital condition known as CAH due to 17-hydroxylase deficiency usually involves replacing glucocorticoid and sex steroid hormones.
Medications like dexamethasone (0.25 to 1.0 mg/day) or prednisone (2 to 5 mg/day) are used to curb the overproduction of ACTH and 11-deoxycorticosterone, leading to decreased levels of mineralocorticoid. This results in better blood pressure and electrolyte levels in the body. Patients are advised to take these medications throughout their lives, but only at the minimum necessary dose that can control ACTH levels. If blood pressure isn’t sufficiently controlled through glucocorticoids alone, blood pressure medications may also be prescribed. Certain medications, like spironolactone, are often chosen because they directly address the excess of mineralocorticoids, but others may also be considered.
In male patients with typical male physical characteristics, testosterone needs to be administered around the time of puberty to ensure proper development of secondary sexual characteristics.
In male patients who physically appear female or in female patients, estrogen/progesterone therapy is required to stimulate the appearance of secondary sexual characteristics. For female patients, this therapy is also necessary for the development of the uterus. Patients who don’t menstruate will need to take these hormones in cycles to induce regular bleeding and prevent the overgrowth of the lining of the uterus.
Regular sex hormone treatment doesn’t typically include DHEA, and instead focuses on testosterone and estrogen/progesterone therapy.
Surgical intervention may be necessary in male patients who physically look female. This might involve removing undescended testes that risk becoming cancerous, and creating female sexual anatomy through a procedure known as vaginoplasty.
Additional fertility treatments may be considered for these patients as they often have difficulty conceiving.
What else can 17-Hydroxylase Deficiency be?
When a doctor is trying to figure out what health problem a patient might have, they often have to consider many different possibilities. With Congenital Adrenal Hyperplasia (CAH), a disorder that affects hormone production, this process can be complicated as there are numerous conditions with similar symptoms:
- Other types of CAH caused by different enzyme deficiencies, for example:
- 21-hydroxylase deficiency
- 11-beta hydroxylase deficiency
- 3 beta-hydroxysteroid dehydrogenase deficiency
- Androgen insensitivity syndrome, a condition that affects sexual development
- 5-alpha reductase deficiency, another disorder related to hormone production
- Various disorders that can affect gender development
Knowing about these possible conditions helps the doctor decide what tests to run or what questions to ask in order to make the correct diagnosis.
What to expect with 17-Hydroxylase Deficiency
With the right combination of medication, including glucocorticoids and sex hormone replacement therapy, both men and women can have a very good outlook. Unlike other types of Congenital Adrenal Hyperplasia (CAH), these patients rarely suffer from serious complications, particularly when it comes to problems like adrenal crisis, or health issues linked to stress, infections, or surgery. Unlike other CAH types, there’s no masculinization, and with treatment, the patient generally develops secondary sexual traits that are suitable.
Those with a deficiency in 17-hydroxylase aren’t at risk for cognitive issues, which can be a problem for people with the common 21-hydroxylase deficiency.
However, there are potential social and emotional challenges linked to incomplete sexual maturation and ambiguous genitalia. This can be a significant concern for these patients over the long run if the condition isn’t identified and treated through proper medical or potentially surgical interventions. Fertility can also be a major issue for these patients as the disease severity may prevent them from having children. They might need comprehensive consultation regarding reproductive health if they wish to have kids. With proper management in the long run, they can lead healthy lives with normal development.
Possible Complications When Diagnosed with 17-Hydroxylase Deficiency
The side effects of 17-hydroxylase deficiency, a condition that affects hormone production, can change based on the severity of the disease and the treatment received. Patients with a severe form of the disease can still experience high blood pressure and low potassium levels despite receiving therapy with a type of steroid medication called glucocorticoids, and may need extra treatment. When the dosage of glucocorticoid therapy is too high, it can lead to symptoms like:
- Obesity
- Skin changes, like stretch marks on the abdomen
- High blood sugar
- Other conditions that also occur with Cushing disease (a disorder that occurs due to high levels of cortisol, a hormone produced by the body).
Preventing 17-Hydroxylase Deficiency
Teaching patients about 17-hydroxylase deficiency, an uncommon genetic disorder, varies depending on the severity of their symptoms. It’s extremely crucial for patients to fully understand their treatment plan and consistently follow it. In some cases, surgery might be an option, so it’s important that this is carefully considered and discussed. Many patients could also benefit from advice about fertility, given this condition can affect reproductive health. Genetic counseling, which can provide insight into how the disorder is inherited, might also be helpful.
