Types of Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia (CAH) refers to a group of genetic disorders that affect the adrenal glands, disrupting the production of essential hormones such as cortisol, aldosterone, and androgens.

This article is a comprehensive guide on the different types of CAH including their causes, symptoms, diagnoses and treatment options, to help patients and families better understand and manage the condition.

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What is Congenital Adrenal Hyperplasia (CAH)?

It’s important to first understand congenital adrenal hyperplasia as an umbrella term for a group of disorders of varying severity, all caused by genetic mutations, and all resulting in adrenal hormone imbalance. 

Understanding Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of inherited disorders that affect the adrenal glands, which produce essential hormones like cortisol, aldosterone, and sex hormones (estrogen and androgens including testosterone and DHEA-S). 

CAH occurs due to genetic mutations that disrupt the enzymes needed for hormone production, leading to hormone imbalances. The most common form, affecting 90-95% of cases, is caused by a deficiency in the enzyme 21-hydroxylase.

CAH can present at birth, childhood, or later, depending on hormone imbalance severity. 

Symptoms range from ambiguous genitalia in female infants and salt-wasting crises to milder cases with menstrual irregularities or infertility. With early diagnosis, treatment, and lifelong management, people with CAH can live healthy lives.

Genetic Basis of CAH

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by mutations in genes that affect hormone production in the adrenal glands. 

Autosomal recessive inheritance means that for a person to have a genetic condition, they must inherit two copies of a faulty gene—one from each parent. If they inherit only one copy, they are a carrier and typically do not show any symptoms.

The most common cause of CAH is a mutation in the CYP21A gene, leading to 21-hydroxylase deficiency. 

Early diagnosis through universal newborn screening and prenatal genetic testing when indicated is essential to diagnose and manage the condition effectively.

Types of Congenital Adrenal Hyperplasia

The specific genetic mutations determine the type of CAH a person inherits.

Classic CAH: 21-Hydroxylase Deficiency

Classic congenital adrenal hyperplasia (CAH) is the most common form of this genetic disorder, caused by a deficiency in the enzyme 21-hydroxylase. 

This enzyme is necessary for producing cortisol and aldosterone in the adrenal glands. When the body can’t make enough cortisol, it leads to an overproduction of androgens (male sex hormones), which can cause abnormal development of sex characteristics. 

There are two main subtypes of classic CAH: salt-wasting and simple virilizing.

Subtypes of Classic CAH

• Salt-Wasting CAH: this is the most severe form of classic CAH. In addition to low cortisol, the body also lacks aldosterone, which helps regulate salt and water balance. This can lead to dangerous salt loss, dehydration, and electrolyte imbalances in infants. 

• Symptoms: symptoms of salt-wasting CAH often appear within the first few weeks of life and include vomiting and poor weight gain. Infant girls also have ambiguous genitalia.

• Simple Virilizing CAH: in this form, aldosterone production is still adequate, but there is still excess androgen production. This causes virilization, which may result in ambiguous genitalia in females and early puberty in both sexes. Unlike salt-wasting CAH, there are no life-threatening electrolyte imbalances.

• Symptoms: infant girls are generally diagnosed earlier. In females, excess androgens can cause ambiguous genitalia (genitalia that don’t look typically male or female). In both males and females, early signs of puberty such as rapid growth and body hair, may appear.

Diagnosis of Classic CAH

Testing for Classic CAH includes:

• Newborn Screening: most countries screen newborns for CAH through a blood test that measures levels of a hormone called 17-hydroxyprogesterone. This can help detect both classic and some nonclassic forms of CAH, and provide life-saving treatment to newborns, especially males who might otherwise go undetected.

• Hormone and Genetic Testing: If CAH is suspected, doctors will confirm the diagnosis with hormone tests and genetic testing to look for mutations in the CYP21 gene. Electrolyte levels, especially with concern for salt-wasting CAH, should also be checked.

Treatment for Classic CAH

• Hormone Replacement Therapy: Treatment involves lifelong use of glucocorticoids (to replace cortisol) and mineralocorticoids (to replace aldosterone in salt-wasting forms). These medications help control hormone levels and prevent further complications. 

• Salt supplements may also be necessary in salt-wasting CAH to maintain proper sodium balance.

• Surgery: in females with significant virilization, surgery may be needed to correct ambiguous genitalia. This is typically done during infancy, but the decision to proceed with surgery should be made carefully, involving both medical professionals and the family.

Non-Classic CAH

Non-classic congenital adrenal hyperplasia (NCCAH) is a milder form of CAH caused by partial enzyme deficiencies in cortisol production. 

Unlike classic CAH, where cortisol and aldosterone deficiencies are severe, patients with NCCAH can still produce enough of these hormones to avoid adrenal insufficiency. The condition is most often due to 21-hydroxylase deficiency and it affects cortisol production pathways, leading to elevated levels of androgens, which can cause symptoms of hyperandrogenism. 

NCCAH is more common than classic CAH and is often diagnosed later in life, during childhood or adulthood.

Symptoms of Non-Classic CAH

Symptoms of non-classic CAH typically include:

• Androgen Excess: in females, this can cause irregular menstruation, acne, excessive hair growth (hirsutism), and fertility issues. In males, symptoms are less common and usually identified through genetic testing.

• Early Puberty: children may experience early signs of puberty, such as body hair development or accelerated growth.

Diagnosis of Non-Classic CAH

• Hormone Tests: diagnosis is based on measuring elevated levels of 17-hydroxyprogesterone and other adrenal hormones. A cosyntropin stimulation test may also be used to confirm the diagnosis.

• Genetic Testing: testing for mutations in the CYP21A2 gene can confirm the diagnosis and help differentiate NCCAH from other conditions.

• Screening: hormonal screening for NCCAH is recommended for individuals with polycystic ovary syndrome (PCOS)-like symptoms since the two conditions can overlap.

Treatment of Non-Classic CAH

• Hormone Therapy: glucocorticoids may be used to control excess androgen production, especially in children with early puberty. Treatment in women with hyperandrogenic symptoms often involves oral contraceptives combined with anti-androgen therapy (e.g., spironolactone) to manage symptoms like acne and hirsutism.

• Monitoring: regular follow-ups are essential to monitor hormone levels and adjust treatment as needed. In patients trying to conceive, glucocorticoid therapy is used to help with ovulation and reduce the risk of miscarriage.

11-Beta-Hydroxylase Deficiency

11-beta-hydroxylase deficiency is a rare form of congenital adrenal hyperplasia, characterized by mutations in the CYP11B1 gene that impair cortisol and aldosterone production. 

This leads to the accumulation of cortisol precursors and excess androgen production, resulting in a variety of clinical manifestations such as virilization of the genitalia, early onset of puberty, and hypertension. 

11-beta-hydroxylase deficiency accounts for 0.2-8% of cases and is more common in certain ethnic populations. Early diagnosis through newborn screening and genetic testing allows for prompt treatment, which is essential for managing symptoms and preventing complications.

Symptoms of 11-Beta-Hydroxylase Deficiency CAH

Symptoms of this rare form of CAH include:

• Androgen Excess: ambiguous genitalia in female newborns (virilization), menstrual irregularities and infertility in females

• Early Puberty: children may experience early pubic hair growth, accelerated bone maturation and short stature

• Persistent Hypertension: in these patients, buildup of a hormone called 11-deoxycorticosterone, which acts like aldosterone, occurs. When too much 11-deoxycorticosterone builds up, it causes the body to retain more salt and water, leading to mild to moderate high blood pressure. 

Diagnosis of 11-Beta-Hydroxylase Deficiency CAH

Diagnostic procedures include:

• Hormonal and Biochemical Testing: elevated 17-hydroxyprogesterone (17OHP), 11-deoxycorticosterone and other androgens are typically found on blood testing. A cosyntropin stimulation test may also be used.

• Genetic Testing: testing for CYP11B1 mutations can confirm the diagnosis and help differentiate NCCAH from other conditions.

• Screening Programs: newborn screening programs for CAH

Treatment of 11-Beta-Hydroxylase Deficiency CAH

• Hormone Therapy: glucocorticoid therapy (e.g., hydrocortisone) to suppress androgen production, and mineralocorticoid replacement if needed for salt-wasting.

• Antihypertensive Medications: these may be prescribed for persistent hypertension

• Surgery: surgery may be required for ambiguous genitalia in select cases

• Monitoring: Lifelong follow-up is necessary to monitor hormone levels and prevent complications. 

17-Alpha-Hydroxylase Deficiency

17-alpha-hydroxylase deficiency is a rare form of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene. It accounts for around 1% of all CAH cases. 

This enzyme deficiency leads to a disruption in the production of cortisol and sex hormones, but aldosterone production may still occur, causing symptoms like high blood pressure and delayed sexual development. 

Unlike more common forms of CAH, it typically presents later in life, as newborn screening does not detect it.

Symptoms of 17-Alpha-Hydroxylase Deficiency CAH

Symptoms of this rare enzyme deficiency may differ between biologically male and female people: 

• 46XX Females: delayed puberty, primary amenorrhea (absence of menstruation), lack of secondary sexual characteristics (e.g., breast development), but with normal female external genitalia.

• 46XY Males: ambiguous genitalia, undescended testes, or incomplete male genital development. They may appear phenotypically female or have underdeveloped male genitalia. Delayed or absent puberty and gynecomastia (breast development) may occur.

• Other Symptoms: high blood pressure (hypertension) and low potassium levels (hypokalemia) due to excess mineralocorticoids.

Diagnosis of 17-Alpha-Hydroxylase Deficiency CAH

Diagnosis often involves:

• Hormone Tests: elevated ACTH levels, low cortisol, elevated deoxycorticosterone, and imbalanced sex hormones. 17-hydroxyprogesterone levels are typically low.

• Genetic Testing: used to confirm mutations in the CYP17A1 gene.

• Imaging: pelvic ultrasound to assess internal genitalia and detect undescended testes in males.

Treatment of 17-Alpha-Hydroxylase Deficiency CAH

Treatment of 17-alpha-hydroxylase deficiency often includes:

• Glucocorticoid Replacement: medications like dexamethasone or prednisone are given to suppress ACTH and reduce excess mineralocorticoid production, helping manage blood pressure and potassium levels.

• Hormone Replacement:

• 46XX Females and Phenotypic Females (46XY): estrogen/progesterone therapy to induce puberty and secondary sexual characteristics.

• 46XY Males: testosterone replacement to induce secondary sexual characteristics.

• Surgery: removal of undescended testes in phenotypic females (46XY) to prevent tumor growth, and vaginoplasty if needed.

• Blood Pressure Management: if glucocorticoid therapy is insufficient, antihypertensives, especially mineralocorticoid antagonists like spironolactone, may be used.

3-Beta-Hydroxysteroid Dehydrogenase Deficiency

3-Beta-Hydroxysteroid Dehydrogenase (3β-HSD) deficiency is another rare form of congenital adrenal hyperplasia (CAH) that affects the production of essential steroids like cortisol, aldosterone, and sex hormones. 

It results from mutations in the HSD3B2 gene, which cause impaired steroid biosynthesis in both the adrenal glands and gonads. 

The condition presents in both salt-wasting (SW) and non-salt-wasting forms, depending on the degree of enzyme deficiency, and causes symptoms related to inadequate hormone production. 

Some patients may also have symptoms of virilization or early puberty, although these are generally not as severe as in other forms of CAH. 

Symptoms of 3-Beta-Hydroxylase Dehydrogenase Deficiency

Symptoms of this rare form of CAH depend on whether the patient has inherited the salt-wasting or non-salt-wasting form.

• Salt-Wasting Form:

• Occurs in newborns, leading to life-threatening salt loss, dehydration, and electrolyte imbalances within the first month of life.

• 46XY males may have ambiguous genitalia and hypospadias (incomplete male genital development) at birth.

• 46 XX females may exhibit mild virilization, such as clitoral enlargement.

• Non-Salt-Wasting Form:

• Less severe, often diagnosed later in life, with milder symptoms.

• Males may have underdeveloped genitalia and hypospadias.

• Females may show premature puberty signs like early pubic hair or acne, but typically have normal genitalia at birth.

Diagnosis of 3-Beta-Hydroxylase Dehydrogenase Deficiency CAH

Diagnostic procedures for this rare form of CAH may include:

• Hormonal Testing: elevated levels of pregnenolone, 17-hydroxy-pregnenolone, and dehydroepiandrosterone (DHEA) indicate 3-beta-hydroxylase dehydrogenase deficiency. A high ratio of Δ5 to Δ4 steroids (precursors) confirms the diagnosis.

• Genetic Testing: identifies mutations in the HSD3B2 gene.

• ACTH Stimulation Test: evaluates adrenal function by assessing the adrenal hormone profile after stimulation.

• Newborn Screening: screening may detect elevated 17-OH-progesterone levels, leading to further testing to differentiate from other forms of CAH.

Treatment of 3-Beta-Hydroxylase Dehydrogenase Deficiency CAH

Treatments for this form of CAH may include: 

• Glucocorticoids: given to replace cortisol and suppress excessive ACTH production, which helps reduce symptoms and manage electrolyte imbalances.

• Mineralocorticoids: for salt-wasting forms, mineralocorticoid replacement is necessary to manage aldosterone deficiency and prevent dehydration.

• Hormone Replacement Therapy:

• Males (46,XY) may require testosterone to induce normal male secondary sexual characteristics.

• Females (46,XX) may need estrogen and progesterone for normal pubertal development and menstrual regulation.

• Surgery: hypospadias repair is often needed for males with ambiguous genitalia. In some cases, gender assignment may need reconsideration later in life.

Genetic Counseling and Family Planning

Genetic testing and counseling is important for people with a personal or close family history of CAH. 

Understanding Inheritance Patterns

CAH is inherited in an autosomal recessive manner, meaning both parents must carry the gene mutation for their child to be affected. Each child of two carrier parents has a 25% chance of having CAH, a 50% chance of being a carrier, and a 25% chance of neither.

Genetic Counseling for Families

Genetic counseling helps families understand the risks for future pregnancies, offering options for prenatal testing and guiding them through the medical and emotional aspects of managing CAH.

Prenatal Testing Options

Prenatal genetic testing can be an option for families at risk of congenital adrenal hyperplasia (CAH). Prenatal testing options for families at risk of congenital adrenal hyperplasia, particularly those who have a known diagnosis or a family history of the condition, include:

• Preconception genetic testing: couples are encouraged to undergo genetic testing before conception, especially if one or both parents are known carriers of CAH. This can help determine the risk of having a child affected by CAH.

• Non-invasive prenatal testing (NIPT): maternal serum cell-free DNA testing can be used as early as 10 weeks of pregnancy to determine the fetal sex. This is important in cases of CAH because virilization occurs in female fetuses with CAH, and early knowledge of the baby’s sex helps guide further testing and management.

• Chorionic villus sampling (CVS): CVS can be performed between 10 to 13 weeks of gestation to definitively diagnose CAH by analyzing placental tissue for genetic mutations in the CYP21A2 gene.

• Amniocentesis: This procedure can be performed later in pregnancy, typically around 15 to 20 weeks, to confirm the presence of CAH in the fetus by analyzing amniotic fluid for genetic mutations.

• Preimplantation genetic testing (PGT-M): for families undergoing in vitro fertilization (IVF), preimplantation genetic testing can identify embryos affected by CAH before they are implanted, helping parents choose unaffected embryos for implantation to avoid passing on the condition.

Prenatal testing allows parents to receive an early diagnosis, enabling informed decisions and preparation for the birth of a child with CAH.