Congenital Adrenal Hyperplasia

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.¹ The second most common cause is deficiency of 11-beta-hydroxylase.² The 21-hydroxylase gene is located on chromosome 6p21 within the HLA histocompatibility complex.³ 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.⁴

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

Neonatal screening for congenital adrenal hyperplasia (CAH) is possible, primarily by detection of persistently elevated 17-hydroxyprogesterone but this is not currently carried out on a national basis in the UK due to the high rate of false positives.⁵ The detection rate can be increased by the addition of molecular analysis.⁶ National screening does take place in the USA and many other countries.⁷

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. 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.⁸
• 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.⁹
• 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.

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.

Nonclassic 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 nonclassic 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.^10,11
• 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 ages³ but this issue is still a matter of debate.¹² Various corrective techniques are available.¹³
• 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 postoperatively and there is a possible increase in susceptibility to adrenal crisis and sudden death.¹⁴

• 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.¹⁵
• 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.¹⁶
• Testicular adrenal rest (accessory adrenal tissue) tumours (TART) are associated with CAH in males and are an important cause of gonadal dysfunction and infertility.¹⁷

1. OMIM; Congenital Adrenal Hyperplasia due to 21-Hydroxylase. Online Mendelian Inheritance in Man.
2. OMIM; Congenital Adrenal Hyperplasia due to 11-Beta-Hydroxylase deficiency
3. Merke DP, Bornstein SR; Congenital adrenal hyperplasia. Lancet. 2005 Jun 18-24;365(9477):2125-36. [abstract]
4. 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. [abstract]
5. Congenital adrenal hyperplasia; National Screening Committee 2009.
6. Silveira EL, Elnecave RH, dos Santos EP, et al; Molecular analysis of CYP21A2 can optimize the follow-up of positive results in Clin Genet. 2009 Dec;76(6):503-10. [abstract]
7. White PC; Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol. 2009 Sep;5(9):490-8. [abstract]
8. The Prader Scale; AboutKidsHealth 2009.
9. 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. [abstract]
10. Antenatal assessment and treatment of women with a previously affected child with Congenital Adrenal Hyperplasia (CYP21) and the subsequent monitoring of outcome parameters post delivery, British Society of Paediatric Endocrinology and Diabetes (2005)
11. Carlson AD, Obeid JS, Kanellopoulou N, et al; Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):19-29. [abstract]
12. Braga LH, Pippi Salle JL; Congenital adrenal hyperplasia: a critical appraisal of the evolution of Eur J Pediatr Surg. 2009 Aug;19(4):203-10. Epub 2009 Aug 19. [abstract]
13. Escala Aguirre JM, Cadena Y, Lopez PJ, et al; FEMINIZING GENITOPLASTY IN ADRENAL CONGENITAL HIPERPLASIA: ONE OR TWO SURGICAL Arch Esp Urol. 2009 Nov;62(9):724-730. [abstract]
14. Gunther DF, Bukowski TP, Ritzen EM, et al; Prophylactic adrenalectomy of a three-year-old girl with congenital adrenal hyperplasia: pre- and postoperative studies. J Clin Endocrinol Metab. 1997 Oct;82(10):3324-7. [abstract]
15. Kim MS, Merke DP; Cardiovascular disease risk in adult women with congenital adrenal hyperplasia Semin Reprod Med. 2009 Jul;27(4):316-21. Epub 2009 Jun 15. [abstract]
16. Krone N, Wachter I, Stefanidou M, et al; Mothers with congenital adrenal hyperplasia and their children: outcome of pregnancy, birth and childhood. Clin Endocrinol (Oxf). 2001 Oct;55(4):523-9. [abstract]
17. Claahsen-van der Grinten HL, Otten BJ, Stikkelbroeck MM, et al; Testicular adrenal rest tumours in congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009 Apr;23(2):209-20. [abstract]

• Wilson TA; Congenital adrenal hyperplasia. eMedicine.com, 2009.
• CaresFoundation; 2009.; Education and support network
• Congenital Adrenal Hyperplasia support group