Your adrenal glands are important endocrine organs that produce hormones that help you cope with stress, balance electrolytes, and maintain balanced stress hormones. Congenital adrenal hyperplasia (CAH) is a genetic disorder affecting the adrenal glands' ability to produce certain hormones.
The genetic changes that cause CAH result in a range of symptoms resulting from deficiencies in the stress hormone cortisol and mineralocorticoid aldosterone and/or too many androgen sex hormones.
Early diagnosis of this genetic disorder is crucial for proper identification of the condition and effective management. This allows for treating symptoms by rebalancing hormones and preventing complications.
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What is Congenital Adrenal Hyperplasia?
Your adrenal glands are endocrine organs located on each side of your back above the kidneys. These glands produce glucocorticoids, mineralocorticoids, and sex steroids to help regulate several important bodily functions.
Cortisol is the main glucocorticoid hormone and helps your body respond to stress, injury, and illness by impacting your stress response and impacting blood pressure, energy, and blood sugar levels. The prominent mineralocorticoid hormone produced by the adrenal glands is aldosterone which helps your body maintain balanced levels of electrolytes like sodium and water to maintain a stable blood pressure and blood volume. The adrenals also contribute to the production of sex hormones like androgens including testosterone that are important for initiating puberty in males and playing an important role in normal growth and development for both sexes.
In CAH, the body lacks a specific enzyme that the adrenal glands need to produce one or more of these hormones. This can lead to imbalances such as too little cortisol, not enough aldosterone, and/or too many androgens.
The majority of cases of CAH are of two main types: classic congenital adrenal hyperplasia and nonclassic congenital adrenal hyperplasia. The classical form can result in a severe deficiency of mineralocorticoids in some cases that results in significant loss of sodium, resulting in shock, coma, and death if not recognized and treated early.
Causes and Genetics of CAH
The various types of CAH are caused by genetic mutations that impact enzymes that normally contribute to the manufacturing of glucocorticoids, mineralocorticoids, or sex steroids from cholesterol by the adrenal glands. All forms have an autosomal recessive inheritance, with one copy of a mutated gene inherited from each parent. This results in both sexes being impacted equally although the clinical presentation varies between sexes due to the impacts of androgens.
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Classic CAH is the most common form occurring in about 1:14,000 to 1:18,000 births. This genetic disorder involves a mutation or deletion of CYP21A that results in a deficiency of the enzyme steroid 21-hydroxylase. This 21-hydroxylase enzyme is essential for the production of all steroid hormones since it is involved in the conversion of 17 hydroxyprogesterone (17 OHP) to 11-deoxycortisol (the precursor for cortisol). It also plays an important role in producing 11-deoxycorticosterone (the precursor of aldosterone) from progesterone.
Almost 300 CYP21A2 mutations have been identified that result in a range of severity of disease with impaired adrenal production of cortisol and often also aldosterone along with the accumulation of adrenal sex steroids like testosterone. Classic CAH is usually diagnosed in infancy and can lead to simple virilizing CAH or salt-wasting CAH.
Nonclassic CAH is usually milder than the classic form of CAH and may be asymptomatic or present with a milder form of virilization after birth. Nonclassic CAH occurs in around 1 in every 100 to 200 people.
In addition to mutations that result in deficiencies of 21-hydroxylase, less common types of CAH occur due to mutations impacting other enzymes that are involved in the production of adrenal hormones. Up to 8% of cases of CAH are due to a mutation in the CYP11B1 gene that results in 11β-hydroxylase deficiency. This enzyme is needed for making cortisol and the androgen dehydroepiandrosterone (DHEA).
Less frequent mutations result in forms of CAH due to 17α-hydroxylase/17–20 lyase deficiency, 3β-hydroxysteroid dehydrogenase deficiency, P450 oxidoreductase deficiency, P450 cytochrome side-chain cleavage deficiency, and StAR deficiency.
Symptoms and Complications of CAH
CAH symptoms vary depending on the type, degree of enzyme deficiency, age, and sex of the patient. The various mutations that lead to CAH cause a shift towards greater androgen production. Appropriate diagnosis is crucial for preventing potentially life-threatening complications such as adrenal crisis and death.
In both salt-wasting and non-salt-wasting forms of classic CAH, an increased level of androgens contributes to typical symptoms. Infants with classic CAH usually have atypical development of the external genitalia with girls showing virilization such as an enlarged clitoris with typical internal female organs and enlargement of the penis in infants assigned male at birth (AMAB) due to exposure to elevated androgens during fetal development. Clues to the diagnosis include ambiguous genitalia or genitals that appear male with non-palpable gonads.
Later on, CAH symptoms can include rapid growth and premature signs of puberty like voice changes, severe acne, and early pubic, armpit, and facial hair. Males with CAH may develop bulky muscles, voice deepening, and excess facial hair as well as noncancerous (benign) testicular tumors. Females may have abnormal menstruation and infertility.
Salt-wasting occurs in both males and females with classic CAH due to not having enough aldosterone. This results in excess salt lost in the urine which can present clinically within a few weeks after birth as failure to thrive and potentially fatal hypovolemia and shock. This type of salt-wasting CAH can result in severe adrenal symptoms ranging from low blood sodium levels (hyponatremia) and dehydration that can lead to low blood pressure (hypotension), irregular heartbeat (arrhythmia), and even shock. Salt-wasting can also cause low blood glucose (hypoglycemia) and too much acid content in your blood (metabolic acidosis) which can cause vomiting, diarrhea, and weight loss.
In the less severe nonclassic form of CAH, milder degrees of enzyme insufficiency leads to excessive sex hormone effects that may not be obvious at birth and occur late in childhood or adolescence. In the most mild forms, symptoms may not be obvious until there are issues with ovulation and fertility in adults. Young women may present with scarce or missing menstrual periods, polycystic ovaries, and abnormal hair growth similar to polycystic ovarian syndrome.
CAH due to a deficiency of 11β-hydroxylase leads to a buildup of androgen hormones.
Depending on the amount of enzyme lacking, cholesterol-derived precursors that are used to form cortisol and corticosterone build up and are converted into androgens, resulting in virilization symptoms and salt retention that can contribute to hypertension.
Diagnostic Testing for CAH
In addition to physical examination to detect physical changes like genital virilization, blood testing can be used to confirm a diagnosis of CAH.
Because of the potentially serious complications of classic CAH, universal newborn screening for CAH is carried out in the U.S. and many developed countries. This is done in the hospital shortly after birth with a heel prick dried blood test to screen for classic CAH by measuring 17 alpha-hydroxyprogesterone (17 OHP) in the blood. 17 OHP blood levels over 242 nmol/L are indicative of classic 21-hydroxylase deficiency. If this screen is positive, a repeat measurement of 17 OHP is obtained along with measuring serum electrolytes.
CAH due to deficiencies in other enzymes such as 11-beta-hydroxylase can be evaluated with liquid chromatography-tandem mass spectrometry.
Blood tests are also available to measure a range of adrenal hormones including cortisol, aldosterone, androgens, and their chemical precursors. In addition, blood testing can measure renin, a hormone that signals the adrenal glands to produce aldosterone, and electrolytes such as sodium which may be low, and potassium which may be elevated in CAH. These electrolytes can also be measured in the urine. Greater levels of sodium and less potassium than usual are lost in the urine with CAH.
In milder cases of CAH, blood levels of 17 OHP may not be initially elevated but will rise when synthetic adrenocorticotropic hormone (ACTH) is administered during an ACTH stimulation test. This test involves measuring blood levels of adrenal hormones before and after an injection of synthetic ACTH is given to signal the adrenal glands to release more cortisol. With CAH, levels of 17 OHP and androgens will increase significantly after ACTH is given.
If classic CAH is suspected in utero due to family history, amniocentesis at 10–12 weeks of gestation or chorionic villous sampling at 15–16 weeks of gestation can be used for the prenatal diagnosis of CAH. If detected in utero, fetal treatment can be implemented by giving dexamethasone to the mother to reduce ACTH hypersecretion in the fetus to avoid genital masculinization in a female fetus with CYP21A2 deficiency.
Nonclassic CAH is often not diagnosed until later in childhood or adolescence when symptoms appear. Hormone testing and ACTH stimulation testing can help confirm the diagnosis.
In addition, a diagnosis of CAH can be confirmed with genetic testing to detect mutations in genes that produce adrenal enzymes.
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Modern Treatments for CAH
The treatments for CAH depend on the type, life stage, and severity of symptoms. Hormone replacement therapy aims to correct hormone imbalances to ensure normal growth and sexual development.
Patients with classic CAH are treated throughout life. Hormone levels are monitored and replacement hormone therapy is given to keep the body in balance. This helps to prevent salt loss and virilization, to achieve normal growth and development in childhood. In adulthood, ongoing treatment helps to ensure normal fertility.
Glucocorticoids are given to replace the cortisol that the adrenals are not making. This treatment with oral glucocorticoids, including prednisolone, hydrocortisone, or dexamethasone, helps to reduce excessive ACTH and the subsequent increase in androgen production that contributes to symptoms.
If needed, mineralocorticoid replacement is also used in those with aldosterone deficiency. Fludrocortisone helps to decrease the amount of sodium lost in the urine to regulate electrolyte and fluid levels in the body.
Treatment for patients with nonclassical CAH is tailored to the specific symptoms and hormone imbalances. For example, acne resulting from excess adrenal androgen production can be countered by giving glucocorticoids like low-dose prednisone (2.5–5 mg/day) or low-dose dexamethasone (0.25–0.75 mg), adjusting the dose to normalize the serum DHEAS level. Ongoing glucocorticoids carry risks of side effects like osteoporosis, so the dose and length of treatment should be limited.
Excessive hair growth (hirsutism) in patients with CAH is treated with anti-androgen medications such as spironolactone, cyproterone acetate, and drospirenone. Alternatively, finasteride, a medication that inhibits the 5alpha-reductase enzyme involved in the production of androgens may be used.
Novel emerging therapies are being developed to help address the hormonal imbalances in CAH with fewer adverse effects. For example, Plenadren is an oral hydrocortisone medication that has an immediate-release coat over an extended-release core to help more closely mimic the normal physiologic fluctuations in cortisol with once-a-day administration. Continuous subcutaneous hydrocortisone infusion (CSHI) therapy has also been developed to mimic circadian glucocorticoid levels using a programmable pump.
Gene therapy is also being studied to address the genetic defects underlying CAH. Adeno-associated virus (AAV) vector-based therapies are being investigated to help replace deficient enzyme functioning to normalize hormone production.
Managing CAH: Lifestyle and Long-term Care
Most of the symptoms of CAH can be managed with ongoing monitoring and individualized treatment. A multidisciplinary care team is crucial for ensuring the most comprehensive and approach care. This approach incorporates endocrinologists, functional medicine providers, dermatologists, psychologists, and other team members to provide care for the whole person and the various aspects of CAH.
Long-term care and individualized treatment integrating conventional medication approaches and lifestyle therapies are important for optimizing outcomes and quality of life. Adrenal crisis occurs when there is insufficient cortisol to respond to stress along with aldosterone deficiency that can lead to shock, dehydration, and life-threatening complications. This life-threatening complication can occur with Infectious illnesses, especially in patients with the salt-wasting form of classic CAH, and is responsible for up to 42% of excess deaths. Patients and their families need to be educated about how to prevent and recognize adrenal crises and about the proper use of stress-dosed glucocorticoids.
In addition to medication to help balance hormone levels, an anti-inflammatory diet rich in a variety of produce, whole grains, and unprocessed proteins like legumes, beans, and wild fish helps to support healthy growth and development. Avoiding processed foods, added sugars, preservatives, and chemical additives can help keep the body balanced. Dietary approaches are also important for maintaining balanced blood sugar levels and avoiding progressive obesity that can occur with long-term glucocorticoid replacement therapy.
Psychological support for the patient and family members can help with the management of this life-long genetic condition. This helps support the individual with the daily management demands of CAH and provides guidance when managing accompanying issues such as gender identity and appearance.
Similarly, enacting meaningful stress management practices as part of holistic self-care is important for people living with CAH. Mind-body practices like yoga, meditation, prayer, and breathing exercises can help balance stress levels.
Physical activity is a powerful way to help manage stress and keep hormones, weight, and blood sugar balanced. Muscle use when exercising prompts glucose uptake to reduce sugar in the blood. This acute response improves insulin sensitivity during and after exercise to improve hormonal balance and counter some of the side effects of steroid therapy. Regular moderate exercise also reduces overall body weight and fat, especially visceral fat, improving overall hormonal function and blood sugar balance.
The Role of Genetic Counseling
Since CAH is caused by genetic mutations that are passed down from parents to their children, genetic counseling and family planning are important. All forms of CAH are inherited in an autosomal recessive manner, so determining the parents’ carrier status can help predict the risk of disease to their offspring. The risks are the same for male or female children.
Genetic counseling can help to evaluate the risk of CAH in families with a history of the condition and guide families in making informed decisions taking into account the future risks of having an affected child. Each parent has two copies of the genes encoding the affected enzymes and passes on one copy each to their child.
If one parent carries an abnormal gene with a CAH mutation, they will not show symptoms of CAH but can potentially pass on the disease to a child. About 1:50–1:71 of the general population carries the gene mutation for CAH due to 21-OHD. When both parents are carriers with one copy of the same mutated gene each, their risk of having a child with CAH is 25%.
On the other hand, if one parent is a carrier with one copy of the mutated gene and one normal copy of the gene but the other parent has CAH with two mutated copies of the gene, their child has a 50% chance of having CAH. If a person with classic CAH has a child with a partner whose carrier status of the 21-OHD CAH mutation is unknown, the chance that the child will have classic CAH is 1 in 120.
Appropriate counseling and family planning incorporate these statistical risks along with consideration of individual values and attitudes. Each couple or individual needs to weigh their own assessment of the risks and benefits of genetic screening and counseling along with experienced professionals.
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Key Takeaways
CAH is a genetic endocrine disorder that results in imbalanced production of hormones from the adrenal glands. This results in deficiencies in the stress hormone cortisol and mineralocorticoid aldosterone which can cause potentially life-threatening symptoms in some cases. CAH can also cause elevated androgen sex hormones that result in virilization, growth and development issues, and fertility impacts.
Early diagnosis and ongoing monitoring of hormone levels are crucial for preventing serious complications. Symptoms can be managed with ongoing hormone replacement and other medications that target imbalances that lead to symptoms like acne and hirsutism. Emerging gene therapy shows promise for correcting the enzyme deficiencies underlying this chronic condition.
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