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Congenital adrenal hyperplasia

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Congenital adrenal hyperplasia is an inherited disorder that results in low levels of cortisol and high levels of male hormones causing development of male characteristics in females, and early puberty in both boys and girls.

What is congenital adrenal hyperplasia?

Congenital adrenal hyperplasia is an inherited condition caused by mutations in genes that code for enzymes involved in making steroid hormones in the adrenal glands.  The most common enzyme defect, 21-hydroxylase deficiency, leads to excess amounts of male hormones being produced by the adrenal gland.

What causes congenital adrenal hyperplasia?

Congenital adrenal hyperplasia results from mutations in the gene that codes for one of several enzymes responsible for making steroid hormones in the adrenal glands.  The most common enzyme to be affected is 21-hydroxylase which is a key regulator in the synthesis of the stress hormone cortisol.  In about two thirds of affected individuals, the enzyme defect in the adrenal may also affect the production of the hormone aldosterone, which is responsible for retaining salt in the body. 

Single mutations in the gene that codes for 21-hydroxylase are very common, affecting one in 50 persons in the overall population.  However, congenital adrenal hyperplasia is a recessive disorder meaning you must inherit a mutation in the gene from both parents in order to develop the condition.  Thus, approximately one in 12,000 babies will be born with congenital adrenal hyperplasia.

In patients with congenital adrenal hyperplasia, the body recognises the lack of cortisol and therefore tries to stimulate the adrenal glands to try to produce sufficient levels.  However, because there is an enzyme defect, the adrenal glands cannot produce cortisol and instead produces excess amounts of precursor steroids.  These precursor steroids are mostly androgenic, ie similar to the male hormone, testosterone.  An excess of male hormones leads to development of male characteristics and precocious (early) puberty.

What are the signs and symptoms of congenital adrenal hyperplasia?

A foetus affected by congenital adrenal hyperplasia will produce excessive male hormones during development.  If the foetus is female, this will result in virilisation of the external genitalia and the female baby may be born with ambiguous genitalia.  As both boys and girls with congenital adrenal hyperplasia have a deficiency of cortisol, they are likely to present in the first few days or weeks of life with an adrenal crisis unless treated with steroid replacement. 

During childhood, the normal healthy child switches off their production of sex steroid hormones.  However, if the infant has untreated congenital adrenal hyperplasia, they will produce excessive levels of male hormones such as testosterone from their adrenal glands.  This will result in rapid growth of both boys and girls, with the additional effect of virilisation of girls.  The adrenal androgens also create an early or precocious puberty with pubic hair growth, body odour, and enlargement of the penis or clitoris at a younger age than would normally be expected.  This can cause early fusion of the bones.  Thus, both boys and girls with poorly controlled congenital adrenal hyperplasia will have rapid growth in early childhood and will be a tall child but a short adult.

In adult life, if the male hormones are not controlled, then a woman will be virilised and in both men and women there might be multiple health problems including infertility and the risk of developing obesity and hypertension due to exposure to excess steroids.  Some individuals with mild forms of congenital adrenal hyperplasia can be diagnosed later in childhood or in adult life.

How common is congenital adrenal hyperplasia?

Congenital adrenal hyperplasia affects 1 in 12,000 live births in most European populations; however, it does vary between different populations and is more common in some. 

Is congenital adrenal hyperplasia inherited?

Congenital adrenal hyperplasia is an inherited condition through mutations in the genes that code for adrenal enzymes.  It is a recessive disorder which means that you need to inherit a mutation from both parents.  Most parents who have a single gene mutation will not be affected by the condition; it is only when you inherit a mutation from both your mother and father that you develop the condition.  There are a variety of mutations, some of which severely affect enzyme activity and others which have only a minor effect.  Thus, there is a variety of severities for the condition.

How is congenital adrenal hyperplasia diagnosed?

Congenital adrenal hyperplasia is usually diagnosed around the time of birth either by a screening test in the newborn, which is done in some countries but not in the UK, or through the clinical presentation.  In a female infant born with ambiguous genitalia, congenital adrenal hyperplasia is often suspected.  If the baby suffers from an adrenal crisis in the first few weeks of life then this will also precipitate the diagnosis.  Children with milder forms (particularly boys) are often diagnosed between two to four years of life with early signs of puberty.

How is congenital adrenal hyperplasia treated?

The goals of treatment for congenital adrenal hyperplasia are to both replace the deficient steroid hormone cortisol and to normalise the excessive male hormone secretion.  This is done by giving steroid hormone therapy, usually in the form of hydrocortisone during childhood, and a variety of steroids in adult life.  The goal of treatment is to optimise growth and development during childhood and maintain fertility and health in adult life.  For children, hydrocortisone is usually given as tablets three times daily.  In adults, hydrocortisone is used in addition to other longer acting steroids such as prednisolone and dexamethasone.  In patients lacking aldosterone production, replacement with fludrocortisone is required to achieve normal salt balance.  

The exact treatment given will vary between patients depending on severity of their condition and the specific genetic mutation they have.  If patients have any queries about their medication, they should discuss them with their doctor.

Are there any side-effects to the treatment?

The major challenge for the treatment of congenital adrenal hyperplasia is the balance between too little or too much steroid hormones.  However, the balance is often difficult to achieve between controlling the condition and giving excessive steroid.  The consequences of excessive steroid treatment are reduced growth during childhood and thin bones, thin skin, obesity and hypertension during adult life. 

Higher doses of hydrocortisone must be supplied for medical emergencies as the body is unable to make its own cortisol in response to stressful situations.   Patients should also carry an intramuscular hydrocortisone injection in case of vomiting, a steroid card and wear Medic-Alert jewellery.

What are the longer-term implications of congenital adrenal hyperplasia?

Patients with congenital adrenal hyperplasia usually have to take lifelong steroid medication.  Current treatment regimens cannot optimally replicate the normal physiological cortisol level, however, there is work being undertaken to try and develop new formulations of hydrocortisone.  The evidence suggests that if well treated during childhood, most patients with congenital adrenal hyperplasia will reach a normal adult height but probably be a little shorter than would have been predicted if they did not have the disorder.  Fertility is reduced in some patients but there are an increasing number of options for helping patients achieve fertility. Reconstruction genital surgery might be required in older girls with ambiguous genitalia.  Maintaining the right balance of steroids is important during adult life to avoid the complications of osteoporosis, obesity and hypertension. 

Although congenital adrenal hyperplasia is a lifelong condition, it can be very successfully treated with the right balance of steroid medication and patients can lead full and active lives.

 

Written: September 2011

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