UNDERSTANDING CONGENITAL ADRENAL HYPERPLASIA: CAUSES, SYMPTOMS, AND MANAGEMENT
Medically Reviewed by Dr. Rae Osborn, Ph.D.
Congenital Adrenal Hyperplasia (CAH) refers to a group of genetic disorders related to adrenal gland function. These glands produce hormones that control various bodily functions. A deficiency causes CAH in one of the enzymes needed to produce cortisol, aldosterone, or both.
Due to a lack of enzymatic conversion, the hormone precursors build up and are directed into androgen production, leading to an overabundance of androgens[1]. Those with the rarest forms have a complete deficiency in all adrenal hormones and their precursors[2]. The condition also leads to adrenal gland enlargement, structural abnormalities in the adrenal glands, and adrenal fat deposits.
CAH is an autosomal recessive disorder, which means that each parent must carry the affected gene in order for their child to acquire the condition. It is estimated that 1 in 10,000-15,000 people are born with CAH in the US and Europe[3], while the prevalence of the mildest forms may be as high as 0.5-1% in the global population[4].
This article examines the symptoms, treatment, and management of CAH and the latest advancements in prenatal testing and diagnosis.
Congenital Adrenal Hyperplasia Types and Causes
There are several types of CAH, each caused by a deficiency in a different enzyme[5]. Enzyme deficiency is most often related to gene mutations.
The cause of over 95% of CAH cases is 21-hydroxylase deficiency related to a mutation in the CYP21A2 gene[6]. This enzyme is critical in producing both cortisol and aldosterone. Less common CAH variations exist, linked to deficiencies in other enzymes involved in hormone production:
- 11-beta-hydroxylase deficiency: This type affects cortisol and ACTH production and can also lead to high blood pressure[7].
- 3-beta-hydroxysteroid dehydrogenase deficiency: This rare CAH form impacts both adrenal and reproductive hormones[8].
- 17-alpha-hydroxylase/17,20-lyase deficiency: Affects cortisol production[9] and sex hormones[10].
- Lipoid CAH: Very severe form, preventing the production of all steroid hormones[11].
Classic CAH
Classic CAH is the most severe form and is typically diagnosed in infancy. In each type, aldosterone and cortisol production are affected, leading to an increase in androgens, such astestosterone.
It has two main subtypes:
- Salt-wasting CAH: This type is the most severe. Potassium levels are elevated and there is a critical lack of both cortisol and aldosterone, which can lead to dehydration, electrolyte imbalances, hyponatremia (low sodium), hypoglycemia, hypovolemia, shock, and potentially life-threatening adrenal crises[12].
- Simple-virilizing CAH (Non-salt wasting CAH): Aldosterone and cortisol production are less affected than salt-wasting CAH, allowing sodium sparing. Excessive androgen production leads to signs of virilization in children.
Nonclassic CAH
All nonclassic CAH types are milder and often diagnosed later in childhood or adulthood. There is enough cortisol and aldosterone production to prevent major crises. Most of the symptoms pertain to an overproduction of androgens[13].
Congenital Adrenal Hyperplasia Symptoms
The symptoms of CAH can vary depending on the type and severity of the condition.
Both classical and nonclassical types induce symptoms of virilization. These signs are more pronounced in the classical types and rarer in nonclassical ones. Many individuals with nonclassical CAH barely notice their symptoms.
Common virilization symptoms in those with CAH include:
- Infertility
- Rapid childhood growth
- Short stature in adults
- Acne
- Early puberty in children
- Excessive hair growth in both males and females
- Well-developed muscles
- Deep voice
Congenital Adrenal Hyperplasia symptoms in females include:
- Ambiguous genitalia in female newborns
- Irregular menstrual periods or amenorrhea (a lack of menstruation)
- Hirsutism (excess male-pattern facial or body hair)
- Fertility problems in about 10% to 15% of women
Signs in males include:
- Enlarged penis with an under-developed scrotum
- Benign testicular tumors
- Male-pattern baldness (hair loss near the temples)
Classical CAH symptoms are usually present at birth or shortly after. Excessive body hair or other pubertal symptoms are evident as early as 2-3 years old in some instances.
Salt-wasting CAH leads to electrolyte imbalances and low sodium (hyponatremia) symptoms in newborns within the first few days to weeks of life. Common symptoms of hyponatremia include:
- Dehydration
- Nausea
- Vomiting
- Weight loss
- Feeding problems
- Headache
- Irritability
- Hypothermia
- Seizures
- Weakness
- Low blood sodium and glucose
- Low blood pressure (hypotension)
- Arrhythmias
If left unaddressed too long, it may lead to an adrenal crisis, a state of shock in which blood does not reach the brain or organs properly. This may result in a metabolic coma and become life-threatening.
If not treated swiftly enough during their infancy, children with classical CAH are at risk of suffering an adrenal crisis throughout their lives when fighting an infection or suffering a physical injury.
Those with simple-virilizing CAH do not suffer from hyponatremia and are not at as much of a risk for an adrenal crisis.
Congenital Adrenal Hyperplasia Diagnosis
Early diagnosis and treatment of CAH are crucial for preventing complications and improving outcomes.
CAH diagnosis occurs through prenatal testing, newborn screening, identifying symptoms, and hormone testing in children and adults.
Diagnosing CAH can be challenging due to the varying nature of symptoms. Prenatal testing, such as amniocentesis and chorionic villus sampling, and newborn screening programs, aid in early detection of CAH.
A detailed family history and a physical examination are crucial diagnostic tools for newborns, children, and adults.
Specific tests used to confirm the diagnosis include[14]:
- Blood tests to measure hormone levels, especially aldosterone, androgen, and cortisol[15].
- Morning 17-hydroxyprogesterone (17OHP) testing can help diagnose the condition in newborns[16].
- The ACTH stimulation test[17] assesses the individual's response to ACTH and whether it stimulates normal cortisol levels.
- Genetic testing[18] to confirm the specific CAH type.
- A hand X-ray to assess the growth rate of a child with CAH[19].
Congenital Adrenal Hyperplasia Treatment and Management
The treatment and management of CAH depend on the type and severity of the condition. The main goals of treatment are to replace the deficient hormones and to prevent complications[20].
Each person with CAH is unique and may require different treatment and management strategies. Healthcare providers need to address individual needs and tailor treatment plans accordingly.
Patients with lesser CAH forms may not require any treatment.
Glucocorticoids
Glucocorticoids, such as hydrocortisone or prednisone, replace cortisol in the body[21]. These medications can contribute to regulating blood sugar levels, reducing inflammation, and maintaining blood pressure.
Chronic glucocorticoid administration can lead to symptoms of Cushing's syndrome[22], such as circadian rhythm disturbances, abdominal weight gain, osteoporosis, poor posture, the development of benign tumors, and symptoms of hyperandrogenism, such as hirsutism. Healthcare professionals may devise a plan that includes breaks from steroids, depending on the severity of the condition.
Mineralocorticoids
Mineralocorticoids, such as fludrocortisone, replace aldosterone in the body[23]. These medications help to regulate salt and water balance, maintain blood pressure, and prevent dehydration.
Anti-Androgens
Anti-androgen medications are often used in the treatment of Congenital Adrenal Hyperplasia
to help regulate the overproduction of androgens[24] and manage symptoms such as excessive hair growth and virilization.
Adrenocorticotropic Hormone Inhibitors
Adrenocorticotropic Hormone (ACTH) receptor inhibitors are emerging as a potential treatment for CAH. By blocking ACTH receptors, these antagonists can reduce adrenal gland overstimulation. This can lead to lower androgen levels[25].
Hormone Replacement Therapy
In females with CAH, some type of hormone replacement therapy may be needed to regulate menstrual periods and improve fertility. Salt Supplements
In cases of salt-wasting CAH, salt supplements can prevent dehydration and low blood pressure. These supplements can be taken as tablets or added to food.
These patients with salt-wasting CAH will also require close monitoring for signs of low blood pressure and hyponatremia, which may require hospitalization.
Surgery
In some cases, surgery can correct genital abnormalities in females with classical CAH. This can involve reconstructive surgery[26] to create a more typical appearance of the external genitalia and to help them function better. Surgery is possible as early as 3-6 months of age, and follow-up surgeries may be necessary later in life.
For men with CAH, they may require surgical removal or ablation of benign testicular tumors.
Living with CAH
Living with CAH can be challenging, but with proper treatment and management, individuals with CAH can lead healthy and fulfilling lives.
It is crucial for individuals with CAH to work closely with their healthcare team and to remain informed concerning the latest advancements in treatment and management.
Routine monitoring to keep track of hormone levels and symptoms is essential for managing CAH. This can help healthcare providers adjust medication dosages and prevent complications.
Other strategies for managing CAH involve[27]:
- Staying adequately hydrated
- Ingesting a balanced, low-fat diet rich in fruits and vegetables
- Avoiding trans-fats and processed foods
- Exercising regularly
- Psychotherapy to help cope with the mental and emotional toll of virilization
Latest Advancements
Advancements in prenatal testing and diagnosis have made it possible to detect CAH earlier than ever before. This allows for early treatment and management, significantly improving outcomes for individuals with CAH.
There are currently glucocorticoid medications approved for adrenal insufficiency that may benefit those with CAH due to having lower corticoid-related side effects. These include[28] [29]:
- Low-dose hydrocortisone granules and tablets
- Dual-release hydrocortisone
- Modified-release hydrocortisone, which is thought by some to be an improvement over dual-release hydrocortisone.
These medications aim to improve upon conventional glucocorticoid therapy by having weaker effects that build, contributing towards a more stable cortisol rhythm and potentially offering reduced side effects. However, studies suggest that some of these medications are not entirely effective at suppressing the early morning ACTH surge (possibly still resulting in Cushing syndrome), and more long-term data is needed to determine their efficacy and safety[30]. However, twice daily modified-release hydrocortisone does appear to control the ACTH surgeStem cell and gene therapies are some of the best potential future treatment options for individuals with Congenital Adrenal Hyperplasia. In a study published in Human Gene Therapy[31], researchers highlight the advancements and potential of these therapeutic approaches.
- Stem Cell Therapies: Stem cells can differentiate into various cell types, including adrenal cells[32]. Researchers are exploring stem cells as a means of generating functional adrenal cells that can replace the deficient cells in individuals with CAH. This approach aims to restore the proper production of hormones, such as cortisol and aldosterone, which are impaired in CAH.
- Gene Therapies: Gene therapy involves modifying the genetic material within cells to correct the underlying genetic mutations responsible for CAH. Scientists are developing strategies to introduce functional copies of the affected genes into the cells, enabling them to produce the necessary enzymes to regulate hormone production. This approach holds promise for providing a long-term solution by addressing the root cause of CAH.
While both stem cell therapies and gene therapies for CAH are still in the experimental stages, they hold great potential for improving the treatment landscape in the future. Continued research and further clinical testing are essential to refinement and to ensure their safety and efficacy before they can be considered as viable treatment options.
Conclusion
Congenital Adrenal Hyperplasia is a complex condition that requires careful management and treatment. With early identification and proper treatment, individuals with CAH can lead healthy and fulfilling lives. Healthcare professionals must stay informed about the latest advancements in prenatal testing, diagnosis, and treatment to provide the best care for their patients.
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