27th May 2025

Congenital adrenal hyperplasia

Background

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders where inherited enzyme deficiencies impair cortisol production. The primary cause is 21-hydroxylase deficiency (21-HD) in 95% of cases, characterised by cortisol deficiency, androgen excess and there may or may not be aldosterone deficiency. hydroxysteroid dehydrogenase deficiency.

Epidemiology

Previous studies have found that CAH affects 1 in 18,000 newborns. Although it affects similar numbers of females and males, males are more likely to present with severe complications such as a salt-wasting crisis. There is an increased prevalence seen in the Ashkenazi Jewish population at 1 in 27.

Aetiology

As an autosomal recessive disorder, CAH most commonly affects the gene encoding 21-hydroxylase (CYP21A2) which is on chromosome 6. The second most common gene affected is that encoding 11-beta-hydroxylase (CYP11B1). As a result of insufficient cortisol production, increased secretion of CRH and ACTH occur, where the latter leads to adrenal hyperplasia and excessive androgen secretion. 

The presentation will vary depending on the severity of mutations present:

• Classical salt-wasting CAH: severe mutations cause females to have virilised atypical genitalia, and severe mineralocorticoid and glucocorticoid deficiency. These can result in salt-wasting crises and adrenal crises respectively.
• Classical simple virilising CAH: moderate mutations result in virilisation, but the ability to retain salt is preserved.
• Non-classical CAH: mild to moderate mutations result in signs of hyperandrogenism but no virilisation of genitalia.

Diagnosis

In classic CAH, diagnosis in female infants can often be found before salt-wasting crisis occurs due to identification of virilised genitalia e.g. clitoral enlargement. However, in male infants, signs will be subtle and therefore diagnosis can be missed until a salt-wasting crisis occurs, presenting with vomiting, dehydration, lethargy, weight loss, hyponatremia and hyperkalaemia. Non-classical CAH presents with precocious puberty (e.g. early pubic hair and advanced bone age) and abnormalities of the gonadal hormones (e.g. oligo/amenorrhea, PCOS, hirsutism and impaired fertility). A positive family history will be common.

First-line investigations include:

• FBC, U&Es, blood glucose: hyponatremia, hyperkalaemia and hypoglycaemia may be seen.
• Serum 17-hydroxyprogesterone: this is a substrate for 21-hydroxylase, and will be high level in 21-HD.
• ACTH stimulation test: gold standard for diagnosis of the non-classic form, where stimulated levels of 17-hydroxyprogesterone are plotted on a nomogram.
• Genetic analysis and karyotyping.
• Ultrasound of pelvis and adrenals.
• Bone age to assess for advanced skeletal maturation.

Management

For classical CAH, the recommended treatment is as follows:

• Glucocorticoid: lifelong glucocorticoids e.g. hydrocortisone prevent further virilisation, and the target dose should maintain physiologic androgen levels.
• Mineralocorticoid: to correct electrolytes and plasma renin activity.
• Sodium chloride: to supplement salt-wasting CAH.
• Growth hormone + gonadotropin releasing hormone analogue: this can be given to infants and children to improve growth rate and final height.
• Genital surgery: this can be offered to remove redundant erectile tissue in virilised females.

For non-classical CAH, the recommended treatment is as follows:

• Glucocorticoid: only recommended for symptomatic non-classical CAH, and when there is risk of premature bone maturation affecting height.
• Growth hormone + gonadotropin releasing hormone analogue: as above.
• Oral contraceptive: can reduce hirsutism.

Complications

Short-term complications include:

• Salt-wasting crisis: hypotension, hyponatremia and hyperkalemia.
• Adrenal crisis: as described in previous sections.

Longer-term complications include:

• Precocious puberty: premature epiphyseal closure and short stature.
• Hyperandrogenism also carries a risk of PCOS, insulin resistance and hypertension.
• Infertility: particularly in forms of classical CAH.
• Side effects related to long-term glucocorticoids: e.g. osteoporosis.
• Testicular adrenal rest tumours: found in males who have undertreated CAH.