Congenital Adrenal Hyperplasia

What is congenital adrenal hyperplasia (CAH)?

Congenital adrenal hyperplasia is an inherited (congenital), lifelong, endocrine (hormone) disorder caused by mutations in genes coding for enzymes in the adrenal gland that synthesise steroid hormones. Patients with CAH have adrenal insufficiency, a deficiency in the stress hormone cortisol. The body’s response to this is to try and drive the adrenal glands harder and they therefore enlarge in size (hyperplasia).

What does the adrenal gland do?

The body has two adrenal glands one sitting above each kidney. The adrenal gland consists of a central portion (the medulla) responsible for the release of adrenaline and the outside layer (the cortex) which is responsible for generating the steroid hormones. There are three classes of steroid hormones secreted by the adrenal cortex and they are: glucocorticoids, important for sugar metabolism, mineralocorticoids important for salt balance, and androgens which are male-type sex hormones. The main glucocorticoid is the stress hormone cortisol, the main mineralocorticoid is aldosterone and the main androgen is testosterone.

What causes congenital adrenal hyperplasia?

CAH results from mutations in the genes that code for enzymes that make steroid hormones in the adrenal gland. The most common enzyme affected is 21-hydroxylase, an enzyme essential for the generation of cortisol and aldosterone. Depending on the severity of the enzyme deficiency, patients with CAH may either have just a deficiency of cortisol or a combined deficiency of cortisol and aldosterone.

Normally, when the brain senses that cortisol levels are low the pituitary gland releases a hormone called ACTH to stimulate the adrenal glands to produce more cortisol, and this switches off as cortisol levels rise. However, in CAH when 21-hydroxylase enzyme activity is compromised or absent cortisol synthesis is reduced or blocked.  The result of this block is the accumulation of cortisol precursors.  In CAH cortisol precursors are diverted instead into the synthesis of androgens.    

Thus, patients with CAH have two problems; a deficiency of cortisol with or without aldosterone deficiency and an excess of adrenal androgens. The excess of male hormone such as testosterone leads to many of the problems experienced by patients with CAH such as virilisation of the female infant, early (precocious) puberty in both boys and girls and infertility in men and women.

Are there different forms of congenital adrenal hyperplasia?

Yes, depending on the severity of the enzyme defect there are different forms of congenital adrenal hyperplasia. In the commonest form of CAH, 21-hydroxylase deficiency these are classified as follows:

Classic: This occurs when there is a severe enzyme defect resulting in cortisol deficiency usually presenting early in life. The classic form is sub categorised into salt-wasting and non- salt-wasting depending on whether the enzyme defect is severe enough to result in a deficiency of the mineralocorticoid aldosterone. Patients who are not salt wasting are also known as simple virilising because they suffer from the excess androgens but not the deficiency in aldosterone.

Non-classic: This is a milder enzyme defect where patients often don’t present until the time of puberty where they might have signs of excess androgen. It is often not diagnosed in men but may be diagnosed in women presenting with problems such as facial hair, irregular periods and infertility.

Who does CAH affect and how common is it?

CAH is a recessive disorder meaning you inherit a mutation in the gene from both your mother and father and you need to have mutation in both genes to develop the disease. Classic CAH occurs approximately in one in every 12,000 live births and affects boys and girls equally, approximately 7 in 10 of these patients have classic salt-wasting CAH.

What are the signs and symptoms of CAH?

Classic CAH usually presents at birth or shortly after birth. Female infants exposed in utero (the womb) to excess male hormones have masculinisation (virilisation) of their external genitalia which can make it difficult to know what sex the baby is immediately (ambiguous genitalia). Therefore, female infants may be diagnosed at birth.

Both boys and girls with classic salt-wasting CAH may present within the first few days of birth with an adrenal salt-wasting crisis. In many countries now there is neonatal screening that will pick up the diagnosis within the first few days of birth if the baby has not already presented.

In cases where the classic simple virilising form of CAH is not picked up by neonatal screening, patients may present within the first couple of years of life with pseudo-precocious puberty, the young child showing excessive growth and development of pubic and axillary hair. Girls with non-classic CAH tend to present around the time of puberty with evidence of virilisation such as hair in a male pattern distribution on the body and irregular periods.

The problems patients with CAH face depends on their age. In childhood, the main challenge is controlling excessive growth and precocious puberty and if this is not well controlled then patients will have an early puberty and ultimately short stature. During early adult life, both men and women may have problems with infertility if the excess androgens are not controlled. Throughout life patients with CAH are prone to adrenal crisis due to their cortisol deficiency.

What current treatments are available for CAH?

The aim of treatment in CAH is to replace the deficient steroid hormone cortisol and to normalise the excessive androgen secretion. This is achieved by replacing the steroid hormone cortisol with a glucocorticoid medicine.. In children hydrocortisone is almost always the glucocorticoid treatment of choice for replacing cortisol, however, in adults longer acting and more potent glucocorticoid hormones such as prednisolone and dexamethasone are also used. Hydrocortisone is usually given three times daily, sometimes with a dose last thing at night and some patients may take it twice daily and some even four times daily. Prednisolone is usually given twice daily and dexamethasone used as a last thing at night treatment. Patients deficient in aldosterone also require replacement therapy with fludrocortisone to achieve normal salt balance.

What are the side effects of treatment?

The major challenge in the treatment of CAH is balancing between giving too little and too much steroid hormone replacement. Too little steroid hormone replacement results in high androgen levels with all its complications in addition to which patients have the symptoms of adrenal insufficiency such as fatigue and a risk of adrenal crisis. Too much steroid hormone results in suppression of growth in children, weight gain, abdominal obesity, hypertension, thin skin, and later in life the risk of cardiovascular disease and osteoporosis. High doses of steroid are needed at times of stress for example when patients have infections but long term excessive steroid exposure results in the above complications.

Further support for people affected by CAH

CAH LogoThe CAH Support Group, Living with CAH exists to provide support to people and families affected by CAH, as well as to increase awareness of the condition to the public and medical profession.

Visit the Living with CAH website for further information and to view their short 3-minute explanatory animation of CAH.