Congenital adrenal hyperplasia (CAH) in neonates

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Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition with an incidence of approximately 1 in 12,500 Caucasian births. It is caused by deficiency of one of a range of enzymes required to make: 

• cortisol, required for stress response, maintenance of blood pressure and essential for life
• aldosterone – required for salt retention
• androgens- for virilization of the fetus (rare form).

Approximately 95 per cent of cases are due to a deficiency of the enzyme 21-hydroxylase (21-OH) which catalyzes the conversion of progesterone and 17-hydroxyprogesterone (17OHP) to deoxycorticosterone and 11-deoxycortisol respectively.

Other rare types of CAH are caused by deficiency of: 11-beta-hydroxylase, 3-beta-hydroxysteroid dehydrogenase, or 17-alpha-hydroxylase (very rare).
Clinical features include:

1. varying degrees of genital ambiguity in the neonate:
   • virilisation in the absence of palpable gonads (the commonest cause of this appearance)
   • under-virilisation (less common and one of a range of possible diagnoses)
2. pigmentation of nipples and genitalia (due to raised ACTH with lack of cortisol)
3. a family history of other affected children, particularly where consanguinity exists. Higher incidence in Asian, African and parental consanguinity populations, and those with other affected siblings.

 This section will focus upon this most common form of CAH, 21 hydroxylase deficiency.

Diagnosis

In the neonatal period CAH due to 21 hydroxylase deficiency may present in one of four ways described below.

1. A virilised female neonate

• With varying degrees of virilisation from minor clitoral enlargement through to complete labial fusion and a ‘male’ appearance but with absence of gonads
• An indication  that neonates with ambiguous genitalia may have CAH is the presence of pigmentation of the areolae and genital skin.
• A family history of parental consanguinity or other affected siblings

2. A male neonate with metabolic and haemodynamic collapse, aged  from a week post birth

• A virilised male infant is usually not detected at birth unless there is unusual pigmentation of scrotal skin, or a family history of previously affected siblings, to alert the staff.
• Presentation can vary from mild (failure to thrive) to catastrophic (sudden infant death). Symptoms include poor feeding, lethargy, weight loss with failure to thrive, progressing to  vomiting and haemodynamic collapse with an impending 'salt losing' adrenal crisis.
• The mortality rate for boys with CAH is thus higher than that of girls.

Frequently, presenting males are assumed to have sepsis or pyloric stenosis. The major clinical indication of CAH is the presence of pigmented genitalia and nature of the electrolyte disturbance. It is unusual for affected females to present in a critical condition, having most commonly been diagnosed in the first few days of life. However, an over-virilised male child is often missed at birth and most frequently presents in this way.

3. Significant metabolic derangement due to adrenal insufficiency

Presentation with these features does not occur in the vast majority of affected infants until the second or third week of life and may occasionally be delayed until weeks 4-8.

Clinical features include recurrent vomiting (which can be mistaken for pyloric stenosis), weight loss, failure to thrive, and haemodynamic collapse.

Biochemical parameters:

• hyperkalaemia
• hyponatraemia
• metabolic acidosis
• hypoglycaemia (rarely).

Milder degrees of CAH may present in more subtle ways (such as isolated clitoromegaly and virilisation in early childhood) and are usually not associated with metabolic compromise in the neonatal period.

4. Antenatally diagnosed case of CAH (due to a previously affected sibling)

Early genetic diagnosis is now available where there is a proband identified in a family. The affected infant is not unwell in utero and only presents post partum, as described above. Given the autosomal recessive nature of the condition, one in four subsequent pregnancies may be affected, with a one in eight risk of an affected female.

Prenatal use of dexamethasone treatment of the mother has been used in the past, to try to reduce virilisation of an affected female fetus but this may have potential adverse effects and is now only used rarely.

Affected female neonates should not be virilised; however, this is not always the case.