Congenital Adrenal Hyperplasia

Group of autosomal recessive disorders of cortisol biosynthesis. 21-hydroxylase deficiency is the cause of about 95% of cases, and is characterised by cortisol deficiency, with or without aldosterone deficiency, and androgen excess.¹ The second most common cause is deficiency of 11-Beta-Hydroxylase.² The 21-hydroxylase gene is located on chromosome 6p21.³ within the HLA histocompatibility complex. The clinical phenotype is classified as:

• Classic: severe form. Sub-classified as salt-losing or non-salt-losing (simple virilising)
• Non-classic: mild or late-onset form

• The severe classic form occurs in 1 in 15 000 births worldwide. The carrier frequency of classic congenital adrenal hyperplasia is about one in 60. Salt-losing congenital adrenal hyperplasia accounts for 67% of the cases reported and non-salt-losing congenital adrenal hyperplasia for 33%.³
• The prevalence of the non-classic form is estimated as one in 1000 in the white population. Non-classic is more frequent in certain ethnic populations, such as Jews of eastern European origin, Hispanics, and Yugoslavs. The mild non-classic form is a common cause of hyperandrogenism.³

• Neonatal screening for CAH and gene-specific prenatal diagnosis are now possible.
• Screening of congenital adrenal hyperplasia is currently not recommended.⁴

Clinical severity depends on the degree of 21-hydroxylase deficiency. The classic forms present in childhood with marked overproduction of glucocorticoids and 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.
• 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 adulthood. 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.

• Other causes of ambiguous genitalia in female neonates
• Other causes adrenal insufficiency
• Other causes of failure to thrive
• Other causes of infertility

• Renal function, electrolytes and blood glucose: hyponatraemia, hyperkalaemia, hypoglycaemia suggest possible adrenal insufficiency.
• Serum 17-hydroxyprogesterone: high level in a random blood sample is diagnostic of classic 21-hydroxylase deficiency. 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.
• Many carriers have slightly raised concentrations of 17-hydroxyprogesterone after a corticotropin stimulation test.

Standard hormone replacement fails to achieve normal growth and development for many children with CAH, and adults can experience iatrogenic Cushing's syndrome, hyperandrogenism, infertility, or the development of the metabolic syndrome.

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, e.g. febrile illness, surgery, trauma:
  • Patients with classic CAH need increased, e.g. 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 patients should wear or carry medical alert identification specifying adrenal insufficiency.

Non-classic CAH

• Many patients 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 adjuvant antiandrogen therapy, e.g. flutamide.
• Patients with non-classic CAH do not need stress doses of hydrocortisone unless they have iatrogenic suppression of their adrenal glands by glucocorticoid treatment.

Prenatal therapy

• In pregnancies in which the fetus is at risk of classic CAH, maternal dexamethasone treatment has successfully suppressed the fetal HPA axis and reduced the genital ambiguity of affected female infants.^5,6
• However prenatal treatment is controversial, since the risk of having an affected female fetus is only one in eight when both parents are known carriers.
• Chorionic-villus sampling or amniocentesis should be done as early as possible. If the fetus is male or a female not affected, treatment is discontinued. For an affected female fetus, treatment is continued throughout pregnancy.

Neonatal period

• Two-thirds of patients 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 controversial. The Joint European Society for Paediatric Endocrinology recommend that surgery should be done in virilised girls with classic CAH at age 2-6 months because it is technically easier than at later ages.³
• Bilateral adrenalectomy: reported long-term (average 5 years) follow-up has revealed improved signs and symptoms of hyperandrogenism and less obesity after surgery. However patients need large amounts of hydrocortisone post-operatively and there is a possible increase in susceptibility to adrenal crisis and sudden death.⁷

• 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 is common in patients with CAH. Insulin resistance is also more common.
• 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 women with CAH who do conceive, the course and outcome of pregnancy is usually not affected.⁸