‘Don’t leap to a conclusion of sepsis!’ Congenital adrenal hyperplasia in male neonates: case series and literature review

Introduction

Hyponatremia, hypoglycaemia and hyperkalaemia occurring in the first few weeks of life in the first instance indicate adreno-cortical insufficiency due to congenital adrenal hyperplasia (salt-losing type).¹ Girls have ambiguous genitalia, while boys may or may not have a large penis at birth. Both boys and girls are asymptomatic for the first few days, after which clinical features develop which include poor feeding, lethargy, vomiting, hypotension and dehydration. The development of severe hyponatremia accompanied by hyperkalaemia and dehydration becomes a life-threatening medical emergency. Consequently, the diagnosis of congenital adrenal hyperplasia (CAH) may not be suggested in male neonates until evident signs of adrenal insufficiency develop. Certain clinical features may, confusingly, commonly suggest neonatal sepsis.

We report two cases to emphasize the importance of establishing a prompt diagnosis of CAH in male neonates, presenting with a clinical picture initially suggestive of neonatal sepsis. Inadequate response due to delayed diagnosis in these cases may result in rapid deterioration and increased morbidity and mortality.

Cases

Discussion

CAH is the most common adrenal disorder presenting in infancy or early childhood; it results in deficiency in any one of the five enzymes required for biosynthesis of cortisol. ² 21-hydroxylase is needed for the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and of progesterone to 11-deoxycorticosterone. Its deficiency accounts for >90% of cases of CAH. The enzyme defect also impairs the conversion of progesterone to aldosterone causing abnormal salt losses. CAH has an autosomal recessive inheritance and is closely linked to the HLA locus on chromosome 6. ³ Worldwide, neonatal screening of babies has shown an incidence of 1:15,000 live births for the classic form of 21-hydroxylase deficiency. ⁴ Differential diagnoses leading to similar results include CAH and other forms of hypoadrenalism, isolated aldosterone deficiency and pseudo hypoaldosteronism (PHA). Classification of CAH into classical and non-classical forms is based on phenotype. ⁵ Both aldosterone and cortisol are deficient in the most severe ‘salt-losing’ form of CAH. Less severely affected babies may synthesize adequate amounts of aldosterone but have elevated levels of androgens of adrenal origin and are known as having ‘simple virilising’ disease. Collectively, these two are called classic 21-hydroxylase deficiency.

Patients of the non-classic form have mildly elevated levels of androgens and have either normal or develop enlarged sexual features at any time after birth. All cases of CAH, including girls with virilisation, have normal sodium and potassium levels at birth and are asymptomatic for the first few days of life. Their chemical abnormalities precede clinical symptoms and signs. Approximately 70% of affected boys present with a salt-losing crisis and develop hyponatraemia, hyperkalaemia, failure to thrive, azotaemia, early metabolic acidosis, increased urinary sodium excretion and hypoglycaemia. ⁶

Diagnosis is made by the detection of extremely high concentrations of basal or stimulated 17-hydroxyprogesterone after performing an ACTH stimulation test. If an ACTH stimulation test is not available or cannot be performed, frank electrolyte abnormalities or haemodynamic instability necessitate the start of immediate treatment without any delay. Molecular diagnosis is confirmed by mutation analysis of the CY21 gene. ⁴ In the classical forms of CAH, basal levels of 17-hydroxyprogesterone are so high that stimulation testing is not needed for diagnosis. In the non-classical forms of adrenal hyperplasia, however, the ACTH stimulation test is required to demonstrate excessive accumulation of precursor steroids.

Managing CAH involves hormonal replacement therapy with corticosteroids to correct the cortisol deficiency. This often requires large glucocorticoid doses, typically 20 mg/m²/day of oral hydrocortisone administered daily in three divided doses. The guidelines for glucocorticoid replacement in CAH suggest the use of short half-life glucocorticoids to prevent adrenal crises and virilisation and longer-acting glucocorticoids to minimise growth suppression.^7,8 During treatment, care should be taken to avoid cortisol excess because this may lead to a Cushingoid syndrome and linear growth suppression. The dose of hydrocortisone must, however, be increased two- to four fold during periods of biological stress such as febrile illnesses, trauma or surgery.

Patients with salt-losing disease require replacement with fludrocortisone, usually 0.1–0.2 mg o.d., and often require sodium supplementation (sodium chloride 0.5–5.0 mmol/kg/day).^9,10 Mineralocorticoid doses vary during infancy owing to improvement in sensitivity which improves with age and particularly during the first year of life. ¹¹ The high mineralocorticoid doses required during infancy are explained by immaturity of renal function, limited sodium content of breast milk, and higher sodium requirement for growth and development.^12,13

Girls with classic 21-hydroxylase deficiency CAH are born with ambiguous genitalia. Those having significant virilisation of genitalia should undergo surgery at the age of 2–6 months.^14,21 Patients usually have a normal life span and normal reproductive potential following surgery and hormone replacement therapy (HRT). ¹⁵

The goal of HRT includes normalising androgen levels and total body sodium depletion for proper growth and development, as well as avoiding volume overload. ¹⁶ Mineralocorticoid needs of salt-wasting 21-hydroxylase deficiency patients are greater during early infancy and progressively decrease during the first two years of life (median fludrocortisone doses are 200 µg at 0–6 months, 150 µg at 7–18 months and 125 µg at 19–24 months), ⁹ and should be based on clinical and laboratory indices such as blood pressure, sodium and potassium levels, and plasma renin activity. ¹⁷ Sodium should be supplemented with 3% saline during infancy. In toddlers and older children, allowing free access to extra salt with meals works well and is also easier.

Possible differential diagnoses include other forms of hypoadrenalism, isolated aldosterone deficiency or PHA.^18,19 Congenital renal anomalies may cause PHA, which may be confused with CAH. ²⁰ The serum aldosterone level helps in alleviating the diagnostic challenge in such cases.

Conclusion

We present these cases to emphasise that the diagnosis of CAH due to 21-hyroxylase deficiency (classic salt-losing type) should always be considered in dehydrated, lethargic male infants with hyponatraemia, hypoglycaemia and hyperkalaemia in the absence of evidence of neonatal sepsis, as prompt diagnosis and early institution of HRT will lead to a successful outcome. Incorrect or inappropriate treatment may result in cardiac arrhythmias, status epilepticus, shock and death in a few weeks or less. ²¹