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A 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. The second most common cause is deficiency of 11-beta-hydroxylase. The 21-hydroxylase gene is located on chromosome 6p21 within the HLA histocompatibility complex. The clinical phenotype has been classified as:
- Classic: severe form. Subclassified as salt-losing or non-salt-losing (simple virilising).
- Nonclassic: mild or late-onset form.
A greater understanding of the genotype-phenotype correlation supports the view, however, that 21-hydroxylase deficiency is a continuum of phenotypes as opposed to a number of distinct phenotypical entities.
- A study found that approximately one child in every 18,000 born in Great Britain has congenital adrenal hyperplasia (CAH). 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 for one quarter.
- The incidence of the nonclassic form is estimated as 1 in 1,000-2,000 in the white population. Nonclassic is more frequent in certain ethnic populations, such as Jews of Eastern European origin. The mild nonclassic form is a common cause of hyperandrogenism.
Neonatal screening for congenital adrenal hyperplasia (CAH) is possible, primarily by detection of persistently elevated 17-hydroxyprogesterone. One study found that around 70% of newborns who first present with salt-wasting crisis in the UK would be detected earlier through newborn screening. 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. National screening is being considered in Australia but it is recommended that it is discontinued in France.
Clinical severity depends on the degree of 21-hydroxylase deficiency. 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 nonclassic congenital adrenal hyperplasia (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 nonclassic CAH have no apparent clinical symptoms and many men with nonclassic CAH remain free of symptoms.
- One study found changes in gender role behaviour, sexuality and psychosocial adaptation in women who had CAH compared to controls.
- 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 of 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 nonclassic congenital adrenal hyperplasia (CAH).
- Corticotropin stimulation test: can be used to assess borderline cases and is the gold standard for diagnosis of the nonclassic 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 congenital adrenal hyperplasia (CAH) and adults can experience iatrogenic Cushing's syndrome, hyperandrogenism, infertility, or the development of the metabolic syndrome.
- 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:
- Patients 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 patients should wear or carry medical alert identification specifying adrenal insufficiency.
- 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, eg flutamide.
- Patients with nonclassic CAH do not need stress doses of hydrocortisone unless they have iatrogenic suppression of their adrenal glands by glucocorticoid treatment.
- 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.
- 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.
- One study showed that children who were exposed to dexamethasone during the first trimester had an impaired verbal working memory which was significantly associated with low self-perceived scholastic competence. In addition, the children showed increased self-rated social anxiety. Larger studies are necessary to evaluate the long-term safety of this treatment.
- Two-thirds of patients with classic CAH are salt-losers.
- Neonates are particularly vulnerable to hypovolaemia and electrolyte disturbances, as well as hypoglycaemia.
- The surgical management of children born with ambiguous genitalia is complex and controversial. One study found that success of surgical outcomes depended on the severity of the disease and that feminising genitoplasty may not be the correct approach for every patient. Further studies on the physical and psychological outcomes of surgical treatment in this condition are needed. Vaginoplasty and clitoroplasty are available for virilised females. Undervirilised males may require treatment of hypospadias or gender reassignment surgery.
- Bilateral adrenalectomy: one study concluded that this was safe and effective in selected patients. Long-term clinical and biochemical follow-up of patients with CAH is needed to detect ectopic adrenal rests earlier (see below).
- The growth and development of many children with congenital adrenal hyperplasia (CAH) is less than optimum. High concentrations of sex steroids induce premature epiphyseal closure and excess glucocorticoids suppress growth.
- Patients with nonclassic 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 women who do become pregnant, delivery is usually by Caesarean section, due to 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.
- Testicular adrenal rest (accessory adrenal tissue) tumours (TART) are associated with CAH in males and are an important cause of gonadal dysfunction and infertility.
Further reading & references
- Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency; Online Mendelian Inheritance in Man (OMIM)
- Congenital Adrenal Hyperplasia due to 11-Beta-Hydroxylase deficiency, Online Mendelian Inheritance in Man (OMIM)
- Huynh T, McGown I, Cowley D, et al; The clinical and biochemical spectrum of congenital adrenal hyperplasia secondary Clin Biochem Rev. 2009 May;30(2):75-86.
- Khalid JM, Oerton JM, Dezateux C, et al; Incidence and clinical features of congenital adrenal hyperplasia in Great Arch Dis Child. 2012 Feb;97(2):101-6.
- Trapp CM, Oberfield SE; Recommendations for treatment of nonclassic congenital adrenal hyperplasia Steroids. 2012 Mar 10;77(4):342-6. Epub 2011 Dec 13.
- Congenital adrenal hyperplasia, National Screening Committee, 2012
- Sarafoglou K, Lorentz C, Otten N, et al; Molecular testing in congenital adrenal hyperplasia due to 21alpha-hydroxylase Clin Genet. 2011 Apr 29. doi: 10.1111/j.1399-0004.2011.01694.x.
- Wu JY, Sudeep, Cowley DM, et al; Is it time to commence newborn screening for congenital adrenal hyperplasia in Med J Aust. 2011 Sep 5;195(5):260-2.
- Coulm B, Coste J, Tardy V, et al; Efficiency of neonatal screening for congenital adrenal hyperplasia due to Arch Pediatr Adolesc Med. 2012 Feb;166(2):113-20.
- Wilson TA, Congenital Adrenal Hyperplasia, Medscape, Sep 2010
- Williams S; Gender confirming surgery in females with congenital adrenal hyperplasia (CAH), Welsh Paediatrics Society, 2008.
- Frisen L, Nordenstrom A, Falhammar H, et al; Gender role behavior, sexuality, and psychosocial adaptation in women with J Clin Endocrinol Metab. 2009 Sep;94(9):3432-9. Epub 2009 Jun 30.
- Congeintal adrenal hyperplasia, Epocrates, 2012
- Ambroziak U, Bednarczuk T, Ginalska-Malinowska M, et al; Congenital adrenal hyperplasia due to 21-hydroxylase deficiency - management in Endokrynol Pol. 2010 Jan-Feb;61(1):142-55.
- Lajic S, Nordenstrom A, Hirvikoski T; Long-term outcome of prenatal dexamethasone treatment of 21-hydroxylase Endocr Dev. 2011;20:96-105. Epub 2010 Dec 16.
- Nordenstrom A; Adult women with 21-hydroxylase deficient congenital adrenal hyperplasia, Curr Opin Pediatr. 2011 Aug;23(4):436-42.
- Hutcheson J et al; Ambiguous Genitalia and Intersexuality, Medscape, Jan 2012
- Kacem M, Moussa A, Khochtali I, et al; Bilateral adrenalectomy for severe hypertension in congenital adrenal hyperplasia Ann Endocrinol (Paris). 2009 Apr;70(2):113-8. Epub 2009 Feb 4.
- Abdel-Rahman M et al, Androgen Excess, Medscape, Mar 2012
- Delfino M, Elia J, Imbrogno N, et al; Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: J Ultrasound Med. 2012 Mar;31(3):383-8.
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Dr Colin Tidy
Dr Laurence Knott
Dr Adrian Bonsall