Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders of cortisol biosynthesis. 21-hydroxylase deficiency (21-OHD) is the cause of about 95% of cases and is characterised by cortisol deficiency, with or without aldosterone deficiency and androgen excess¹. The second most common cause is deficiency of 11-beta-hydroxylase². The 21-hydroxylase gene is located on chromosome 6p21 within the HLA histocompatibility complex¹. The clinical phenotype has been classified as:

• Classic: severe form. Subclassified as salt-losing or non-salt-losing (simple virilising).

• Non-classic: mild or late-onset form.

An increase in the understanding of the genotype-phenotype correlation suggests, however, that 21-OHD may be a continuum of phenotypes rather than a number of distinct phenotypical entities.

Epidemiology

The most common form is 21-OHD, accounting for more than 90% of all cases³. According to newborn screening data, classic 21-OHD affects 1 in 10,000 to 1 in 15,000.

A study found that approximately 1 child in every 18,000 born in Great Britain has CAH⁴. Similar numbers of boys and girls present clinically in the first year of life but boys present with more severe manifestations, such as salt-wasting crises. Salt-losing CAH accounts for about three quarters of cases reported and non-salt-losing CAH (NCAH) or one quarter.

The worldwide prevalence of NCAH among hyperandrogenic women was 4.2% (95% confidence interval: 3.2-5.4%) and is more frequent in certain ethnic groups, such as the Ashkenazi Jewish population⁵.

Screening

Screening of neonates with elevated 17-hydroxyprogesterone concentrations for classic (severe) 21-OHD is in place in many countries; however, this is not currently carried out on a national basis in the UK due to the high rate of false positives. The detection rate can be increased by the addition of molecular analysis, and cosyntropin stimulation testing might be needed to confirm the diagnosis or establish non-classic (milder) subtypes⁶.

A large study from France raised questions about the organisation of many screening programmes, showing results in preterm neonates to be significantly less reliable, and found a debatable effect on mortality overall⁷. A study in Sweden, however, found neonatal screening had reduced mortality due to early detection of the salt-wasting form⁸.

Presentation⁹

Clinical severity depends on the degree of 21-OHD. The classic forms present in childhood with marked underproduction of glucocorticoids and overproduction of adrenal androgens. In the most severe form, aldosterone deficiency leads to loss of salt. In the mildest form, there is sufficient cortisol production but at the expense of excess androgens.

• Female infants with the classic form: ambiguous genitalia with an enlarged clitoris and a common urogenital sinus in place of a separate urethra and vagina. The internal female organs are normal. Because of the ambiguous genitalia, girls with the salt-losing form are usually diagnosed before they experience a salt-losing adrenal crisis in the neonatal period. A staging system (Prader scale 1-5) has been developed to categorise the severity of the genital abnormalities in girls. This is helpful in determining whether corrective surgery should be considered.

• Boys with classic form: no signs at birth, except subtle hyperpigmentation and possible penile enlargement. The age at diagnosis depends on the severity of aldosterone deficiency.

• Boys with the salt-losing form typically present at 7-14 days of life with vomiting, weight loss, lethargy, dehydration, hyponatraemia and hyperkalaemia and can present in shock.

• Boys with the non-salt-losing form present with early virilisation at age 2-4 years.

• Patients with the non-classic CAH present with hyperandrogenism in later childhood or in early adulthood⁵. These patients can present with early pubarche, or as young women with infertility, hirsutism, oligomenorrhoea or amenorrhoea with polycystic ovaries and acne. Some women with non-classic CAH have no apparent clinical symptoms and many men with non-classic CAH remain free of symptoms.

• Carriers usually have no symptoms or signs of excess androgens and do not need treatment.
  

Differential diagnosis

• Other causes of ambiguous genitalia in female neonates.

• Other causes of adrenal insufficiency.

• Other causes of failure to thrive.

• Other causes of infertility.

• Polycystic ovary syndrome.

Investigations¹⁰

• Renal function, electrolytes and blood glucose: hyponatraemia, hyperkalaemia and hypoglycaemia suggest possible adrenal insufficiency.

• Serum 17-hydroxyprogesterone: high level in a random blood sample is diagnostic of classic 21-OHD. False-positive results from neonatal screening are common with premature infants and so reference ranges are based on weight and gestational age. An early-morning measurement can be used for screening but it is not as sensitive or specific as a corticotropin stimulation test. Levels may be normal in patients with non-classic CAH.

• Corticotropin stimulation test: can be used to assess borderline cases and is the gold standard for diagnosis of the non-classic form.

• Pelvic ultrasound in an infant with ambiguous genitalia to demonstrate presence or absence of a uterus and any associated renal anomalies.

• Bone age: useful in evaluating a child with precocious pubic hair, clitoromegaly or accelerated linear growth (children with adrenal hyperplasia who develop these symptoms have advanced skeletal maturation).

• Karyotype: in the evaluation of an infant with ambiguous genitalia to establish the patient's chromosomal sex.

• Genetic analysis can be helpful to confirm the diagnosis. This is recommended only where diagnosis is equivocal, or where genetic counselling is needed.

Management¹⁰

Management depends on the age of presentation, and the type and severity of CAH.

Classic CAH

• Glucocorticoids: hydrocortisone is the glucocorticoid of choice during childhood. Longer-acting glucocorticoids, such as prednisolone and dexamethasone, can be used in adults but they are generally avoided in children because of concerns about growth suppression.

• Mineralocorticoids: to control electrolytes and plasma renin activity. Mineralocorticoid replacement is achieved with fludrocortisone.

• Infants with salt-losing CAH often need sodium chloride supplementation. Routine salt supplementation is not usually needed after the first 6-12 months of life. Additional salt intake may be needed with exposure to hot weather or with intense exercise.

• Treatment during physical stress - eg, febrile illness, surgery, trauma:
  

  • People with classic CAH need increased (eg, doubling or tripling) doses of hydrocortisone.

  • Intravenous hydration may be required.

  • Hypoglycaemia may occur with exercise, illness or fasting. Intake of carbohydrates and glucose should be increased.

• All those on glucocorticoids should wear or carry medical emergency identification specifying adrenal insufficiency.

It is currently unclear whther one gluococrticoid replacement regime is superior to any other¹¹.

Non-classic CAH

• Many do not need treatment. Treatment is recommended only for those with symptoms. Glucocorticoid treatment is indicated in children with androgen excess, whereas adult women may need female hormones via the contraceptive pill, or adjuvant antiandrogen therapy - eg, flutamide.

• People with non-classic CAH do not need stress doses of hydrocortisone unless they have iatrogenic suppression of their adrenal glands by glucocorticoid treatment.

• Those who have been treated should be given the option of stopping treatment when symptoms resolve.

Prenatal therapy

• When a pregnant woman has classical CAH, dexamethasone treatment is recommended to suppress the fetal HPA axis and reduce the genital ambiguity of affected female infants¹⁰.

• However, the risk of having an affected female fetus is only 1 in 8 when both parents are known carriers.

Neonatal period

• Two thirds of people with classic CAH are salt-losers.

• Neonates are particularly vulnerable to hypovolaemia and electrolyte disturbances, as well as hypoglycaemia.

Surgical

• The surgical management of children born with ambiguous genitalia is complex and depends on the severity of the disease and that surgery may not be the correct approach for every patient. Early surgery should be considered for severely affected infants and carried out only by experienced specialist teams. Vaginoplasty and clitoroplasty are available for virilised females.

• Bilateral adrenalectomy is very occasionally indicated in exceptional cases but carries lifelong risks.

Complications⁶

• • The growth and development of many children with CAH is less than optimum. High concentrations of sex steroids induce premature epiphyseal closure and excess glucocorticoids suppress growth.

  • Patients with non-classic CAH have a more favourable height prognosis than those with the classic form.

  • Obesity, insulin resistance and hypertension are all more common in patients with CAH, raising the risk of cardiovascular disease. In women, hyperandrogenism compounds this risk.

  • Central precocious puberty, which is most likely to develop when the diagnosis of CAH is delayed or with poor control of adrenal androgen secretion.

  • Increased incidence of polycystic ovaries.

  • Infertility: fertility is reduced in females with CAH, especially those with the severe or salt-wasting phenotype. In non-classic 21-hydroxylase deficiency, pre-conceptional low-dose hydrocortisone replacement normalises the otherwise increased miscarriage rate³.

  • In women who do become pregnant, delivery by caesarean section might be needed because of vaginal stenosis or an android pelvis. Virilisation of female infants born to mothers with CAH has not been reported but is a possibility in uncontrolled cases.

  • Side-effects and consequences of long-term glucocorticoid therapy.

  • Testicular adrenal rest (accessory adrenal tissue) tumours (TART) are associated with CAH in males and are an important cause of gonadal dysfunction and infertility.