What Is Congenital Adrenal Hyperplasia?

Congenital adrenal hyperplasia (CAH) is a group of disorders characterised by the inability of the adrenal gland to produce steroid hormones such as cortisol.^1,4 Congenital means the disease is present from birth, and hyperplasia means the affected organ is larger than usual. Congenital adrenal hyperplasia is an autosomal recessive genetic condition, which means both parents have the mutated gene and the child inherits both copies.⁶ CAH is the most common inherited form of primary adrenal insufficiency (where the adrenal glands cannot produce enough steroid hormones).^12,15

Congenital adrenal hyperplasia is caused by mutations of the genes that make the enzymes involved in producing steroid hormones.^2,3 The most common involves the 21-hydroxylase enzyme.^4,12 Deficiencies in other enzymes may cause CAH, though this is much rarer. 

Steroid hormones include corticosteroids (such as cortisol), mineralocorticoids (such as aldosterone), and androgens (such as testosterone).⁹ These hormones play key roles in regulating the immune system, body metabolism, and salt and water balance. Their deficiency results in symptoms such as ambiguous genitalia, infertility, excessive body hair, irregular periods, and premature onset of puberty.⁵ The severity of symptoms is influenced by the level of mutation in the genes of the affected enzyme and may affect cortisol production only or both cortisol and aldosterone production.²⁷ There is no cure, though individuals can live normal lives when treated with appropriate hormonal replacement therapy. ^{20, 23}

Overview

The adrenal glands are a pair of triangular-shaped organs situated on the upper part of the kidneys.^7,11 The adrenal gland is made up of the cortex and medulla.⁹ The cortex produces steroid hormones including glucocorticoids, mineralocorticoids, and adrenal androgens (and the medulla produces the hormones epinephrine (adrenaline) and norepinephrine (noradrenaline)).^8,10 Glucocorticoids play key physiological roles in metabolism, water and electrolyte balance, immune response, growth, cardiovascular function, mood, cognitive functions, reproduction, and development.^13,14 Mineralocorticoids are crucial in the regulation of salt and water balance.^15,16,17 The adrenal androgens are important for the early development of the male sex organs in childhood, and the onset of body hair in people assigned female at birth (AFAB) during puberty.^18,19

Types of congenital adrenal hyperplasia

There are two types of congenital adrenal hyperplasia.^4,20,21

Classic congenital adrenal hyperplasia 

Classic congenital adrenal hyperplasia is usually diagnosed at birth and can be fatal if untreated. Classic CAH has two subtypes:

• Salt-wasting congenital adrenal hyperplasia: Salt-wasting is the most severe form of congenital adrenal hyperplasia. It accounts for 75% of classic CAH cases.³² The adrenal glands produce very little mineralocorticoids (aldosterone) and glucocorticoids (cortisol) while producing excess androgen. As a result, the body gets rid of too much sodium in the urine, and cannot retain enough for normal function.
• Simple-virilizing congenital adrenal hyperplasia: This form accounts for 25% of classic CAH cases. The adrenal glands also produce very little mineralocorticoids (aldosterone) and glucocorticoids (cortisol) while producing excess androgen, but all these are at less severe levels.

Non-classic congenital adrenal hyperplasia 

Non-classic congenital adrenal hyperplasia is milder and more common than the classic form. It is often diagnosed in later childhood or early adulthood. This type tends to be asymptomatic (have no symptoms) in people assigned male at birth (AMAB), while in people AFAB it can cause symptoms such as excess body hair, early puberty, and irregular periods.

Causes of CAH

Deficiency of the 21-hydroxylase enzyme is caused by deletions and mutations in the CYP21A2 gene on chromosome 6.^20,21

Normally when cortisol levels are low, feedback is sent to the brain through the hypothalamic-pituitary-adrenal (HPA) axis, triggering the pituitary gland to release a hormone called adrenocorticotropic hormone (ACTH) which then stimulates the adrenal glands to produce more cortisol.^23,24 21-hydroxylase is an enzyme involved in making cortisol and aldosterone. In congenital adrenal hyperplasia, levels of 21-hydroxylase are either insufficient or its action is blocked, resulting in the accumulation of cortisol precursors, which the body then diverts into the production of androgens. The result is the underproduction of cortisol, with or without aldosterone deficiency, and the overproduction of adrenal androgens. 

Signs and symptoms of CAH

Signs and symptoms of CAH can vary greatly, from mild to potentially fatal, depending on the form of the disease.^4,31,32

Salt-wasting classic congenital adrenal hyperplasia 

Symptoms of salt-wasting classic CAH include: 

• Vomiting 
• Weight loss 
• Dehydration 
• Diarrhoea 
• Low blood sugar 
• Low blood pressure 
• Irregular heartbeat (arrhythmia)
• High acid content in the blood (metabolic acidosis)

Simple virilizing classic congenital adrenal hyperplasia

Symptoms of simple-virilizing classic CAH include: 

• Ambiguous genitalia (external male organs and internal female organs) 
• Enlarged penis
• Small testicles
• Irregular menstrual periods
• Premature onset of puberty (e.g., deep voice, acne, and excess hair in the pubic, armpit, and facial areas)
• Infertility

Non classic congenital adrenal hyperplasia 

Symptoms of non-classic CAH include: 

• Fast growth (tall for age as children but may eventually be short as adults if treatment is not started early)
• Male-pattern baldness
• Irregular menstrual periods 
• Premature onset of puberty 
• Infertility

Management and treatment for CAH

Management depends on the age of presentation, the type, and severity of congenital adrenal hyperplasia.²⁸ Patients should wear or carry a medical alert identification specifying adrenal insufficiency.²³

The mainstay of treatment is glucocorticoid replacement.³¹ Hydrocortisone is preferred for children, while prednisolone and dexamethasone are used in adults. Mineralocorticoid replacement is done with fludrocortisone. During times of increased physical stress such as febrile illness (any illness that causes a fever), surgery, trauma, or exercise, glucocorticoid doses are usually doubled or tripled.⁴ Lifelong follow-up is needed to monitor the doses of glucocorticoids and mineralocorticoids, as well as to monitor the potential side effects arising from their use.^3,28 

Aside from hormone replacement, management for CAH may also include intravenous hydration and changes in diet. Adequate intake of carbohydrates and glucose is essential to prevent low blood sugar (hypoglycaemia). Further, the management of ambiguous genitalia should involve a multi-disciplinary team (which includes specialists in paediatric endocrinology, paediatric urology/surgery, clinical genetics, and clinical psychology).³ Pregnant people with classical congenital adrenal hyperplasia are treated with dexamethasone. This should be started before eight weeks of pregnancy to prevent the genital ambiguity of affected female infants. ²³

Diagnosis of CAH

Initial screening for CAH measures levels of the cortisol precursor 17-hydroxyprogesterone in the blood.²⁸ Other investigations include a serum testosterone assay, rapid ACTH stimulation test, checking levels of serum cortisol, and checking levels of serum 11-deoxycorticosterone (a precursor to aldosterone).^23,33 Depending on the findings, a pelvic and adrenal ultrasound may be done. ³³ Genetic testing and counselling are usually done during pregnancy. ²³

Risk factors of CAH

Risk factors include:

• Family history: parents who both have congenital adrenal hyperplasia or are carriers
• Race: Ashkenazi Jewish, Mediterranean, Latino, Yupik, or Yugoslav ancestry have a higher risk of CAH^20,33,34

Complications of CAH

Complications may either be due the disease (low steroid levels and high androgen levels) or to medications that result in an excess of glucocorticoids and mineralocorticoids.^4,28,29,30 

Complications due to high androgen levels include: 

• Irregular heartbeat (arrhythmia) 
• Cardiac arrest 
• Short stature
• Infertility 
• Adrenal insufficiency
• Adrenal crisis 

Complications due to excess gluco- and mineralocorticoids include: 

• Weight gain 
• Abdominal obesity 
• Cardiovascular disease 
• Osteopenia
• Osteoporosis

FAQs

How can I prevent CAH?

Congenital adrenal hyperplasia cannot be prevented as it is a genetic condition.

How common is CAH?

Congenital adrenal hyperplasia affects approximately one in every 18,000 children born in Great Britain.²² The classic form occurs in 1 in every 15,000 births worldwide, while the non-classic form occurs in approximately 1 in every 1,000 births.²⁶ Congenital adrenal hyperplasia equally affects both boys and girls, though symptoms are more severe in boys.²⁵ Newborn screening for CAH is not recommended in the UK because of the high number of false positives and false negatives, and babies may develop symptoms before receiving test results.²⁷

When should I see a doctor?

You should see your doctor if you are worried about your child's growth or development.

Summary

Congenital adrenal hyperplasia (CAH) is a group of genetic hormonal disorders characterised by the inability of the adrenal glands to make steroid hormones. Congenital adrenal hyperplasia affects approximately one in every 18,000 children born in Great Britain. CAH is most commonly caused by mutations in the genes that code the 21-hydroxylase enzyme. Symptoms include ambiguous genitalia, infertility, excessive body hair, irregular periods, and premature onset of puberty. CAH cannot be prevented as it is a genetic condition. You should see your doctor if you are worried about your child's growth or development. There is no cure, though individuals can live normal lives when treated with appropriate hormonal replacement therapy.