Congenital adrenal hyperplasia

Author: Dr Giri Raj, Dermatology Registrar, Middlemore Hospital, Auckland, New Zealand, 2009.


What is congenital adrenal hyperplasia?

The term congenital adrenal hyperplasia refers to enlarged adrenal glands. It is due to inherited enzyme deficiency. Congenital adrenal hyperplasia is the most common adrenal disorder of infancy and childhood.

Congenital adrenal hyperplasia results excessive androgens (male hormones). There is also a severe salt-losing form of the condition.

How does congenital adrenal hyperplasia arise?

An enzyme deficiency may result in a failure of the adrenal glands to make normal amounts of cortisol. The decrease in cortisol level stimulates the pituitary gland to release adrenal corticotrophic hormone (ACTH). ACTH makes the adrenal gland enlarge and produce more cortisol, mineralocorticoids and androgens.

  • Cortisol is a glucocorticoid. Glucocortocoids have multiple actions on many organ systems. They increase liver glucose output, cause atrophy of type II muscle fibres, inhibit bone formation, reduce calcium absorption in the gut, increase cardiac output, increase blood pressure and increase lung maturation. They also cause insulin resistance, modulate the thyroid axis and reduce the number of circulating lymphocyte cells.
  • The major minerolocorticoid is aldosterone. This acts on the kidneys to reabsorb sodium and water into the blood stream, and to secrete potassium into the urine.
  • The adrenal androgens are dehydroepiandrosterone (DHEA), androstenedione and 11-hydroxyandrostenedione. These are weak androgens and are converted to the more potent androgen testosterone in other tissues, including the skin. Androgens regulate sexual homone secretion by the hypothalamic–pituitary system (gonadotropins) and regulate the formation of male characteristics during puberty.

Congenital adrenal hyperplasia may be contrasted with Cushings Syndrome, in which there is excess cortisol. When this is due to excess ACTH, the adrenals also enlarge and produce more adrenal androgens.

What enzymes are involved?

Congenital adrenal hyperplasia may be due to:

  • 21-hydroxylase deficiency
  • 17-hydroxylase deficiency
  • 3β-hydroxysteroid dehydrogenase deficiency
  • Partial enzymes deficiencies.

The clinical signs of congenital adrenal hyperplasia depend on which enzyme is lacking and to what extent.

21 hydroxylase deficiency

21-hydroxylase deficiency or classic congenital hyperplasia accounts for most cases (95%). It may cause health problems in the newborn period or not until puberty or later. The enzyme deficiency reduces cortisol, increases androgens, and in one-third of cases, reduces aldosterone production.

21-hydroxylase deficiency may present in the first two weeks of life. It may present as ‘salt-losing’ acute adrenal insufficiency or as genital ambiguity in females. Partial 21-hydroxylase enzyme deficiency is less severe. It is more likely to present in later childhood or adolescence with signs of androgen excess.

Clinical features of 21-hydroxylase deficiency
Acute adrenal insufficiency
  • Due to lack of cortisol and aldosterone
  • High blood pressure
  • Salt-craving
  • Dehydration
  • Vomiting
Genital ambiguity
  • Due to excess androgens
  • Affects females only
  • Known as ‘female pseudohermaphroditism’
  • Enlarged clitoris
  • Partial or complete fusion of labia
  • External genitalia may resemble a penis
Late onset in females
  • Virilisation: deepened voice, small breasts, increased muscle bulk, enlarged clitoris, increased libido
  • Accelerated bone age
  • Absent or irregular menstrual periods
  • Male pattern of hair growth (hirsutism)
  • Oily skin (seborrhoea)
  • Acne
  • Androgenetic alopecia
Late onset in males
  • Premature puberty
  • Accelerated bone age
  • Enlargement of testes, due to adrenal tissue growing within the testes

How is the diagnosis made?

The diagnosis should be considered in infants presenting with acute adrenal insufficiency, with virilisation (females) or premature puberty (males).

Initial tests in acute adrenal insufficiency reveal a salt-losing state.

  • Low levels of sodium (hyponatraemia)
  • High levels of potassium (hyperkalaemia)
  • Low serum aldosterone
  • Low serum cortisol
  • High plasma renin

21-hydroxylase deficiency is diagnosed by finding high levels of the following hormones in blood or urine:

  • Serum 17-hydroxyprogesterone
  • Plasma DHEA sulphate
  • Urine pregnanetriol
  • Urine 17-ketosteroids

Adrenal ultrasound scan may be carried out if the baby’s genitals appear abnormal on birth.

Genetic tests may be available to identify the specific genetic mutation.

Prenatal diagnosis

Genetic testing may be considered during pregnancy if an unborn infant is known to be at risk because a sibling is affected or if both parents are known to carry the abnormal gene. Genetic tests performed during pregnancy include:

  • Chorionic villus sampling at the 8th week
  • Amniocentesis at the 12th week

Prenatal diagnosis may also be made by finding increased levels of 17-hydroxyprogesterone in amniotic fluid at 14 weeks of gestation.

Treatment of classic congenital hyperplasia

Treatment of classic congenital hyperplasia aims to replace glucocorticoid (cortisol) to prevent excessive ACTH secretion, using a small dose of dexamethasone, usually 0.5mg at nighttime.

The levels of circulating androgens may be reduced by antiandrogen treatment. Available drugs include:

In the salt-losing form of congenital adrenal hyperplasia, mineralocorticoid, usually fludrocortisone at a dose of 0.1 mg, is given to maintain normal extracellular fluid volume and electrolyte levels. Blood pressure, electrolytes and plasma renin activity are monitored to assess the response.

17-hydroxylase deficiency

17-hydroxylase deficiency is rare. It presents at puberty because of reduced andrenal androgen production (hypogonadism).

  • Females with 17-hydroxylase deficiency present with delayed puberty: they do not menstruate, and breasts and pubic hair fail to develop.
  • Males present with ambiguous external genitalia or appear to be female (male pseudohermaphroditism).

17-hydroxylase deficiency causes decreased production of cortisol and increased mineralocorticoids. Tests reveal:

  • High blood pressure (hypertension)
  • Low potassium
  • Low plasma renin
  • Low urinary 17 ketosteroid
  • High urinary gonadotropin

Treatment is with dexamethasone to correct the hypertension and testosterone to accelerate sexual maturation.

3-Beta hydroxysteroid dehydrogenase deficiency

3β-hydroxysteroid dehydrogenase deficiency reduces production of all adrenal steroid hormones (cortisol, aldosterone, androgens and oestrogens). It presents in early infancy with vomiting, salt wasting and genital ambiguity. Tests reveal:

  • Low sodium
  • High potassium
  • High urinary DHEA
  • Low urinary cortisol metabolites (namely 17 hydroxycorticosteroid).

Conversion of pregnenolone to progesterone is impaired, blocking synthesis of both cortisol and aldosterone but increasing adrenal androgens. In females these weak androgens produce partial virilisation.

3β-hydroxysteroid dehydrogenase deficiency reduces testosterone production in the male testis so that the genitals of a male may be incompletely formed.

Treatment is replacement of glucocorticoids, fludrocortisone and sex steroids from puberty onwards.

 

Related Information

References:

  • Willams, G, Dluhy, R. 2005. Disorders of the adrenal cortex. In Kasper,D and Fauci, A and Longo,D. Harrison’s principles of Internal Medicine, 16th edn, 259-279. Magraw-Hill Companies Inc,USA.
  • Fitzgerald, P. 2005. Endocrinology. In Tierney,L and McPhee,S and Papadakis,M. Current medical diagnosis and treatment, 44th edn, 1127-1137. Lange Medical Books, New York.
  • Basic and Clinical Endocrinology. Greenspan and Gardener, 7th edn, 2004, page 535-45.
  • Merke,DP. Bornstein,SR. Congenital Adrenal Hyperplasia. Lancet 2005; 365:2125.
  • Miller, WL. Genetics, diagnosis, and management of 21-hydroxylase deficiency. J Clin Endocrinol Metab 1994; 78:241.

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