Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia is a group of autosomal recessive disorders of adrenal steroidogenesis. Each results from deficiency of one of the enzymes needed for normal cortisol (and, in most subtypes, aldosterone) biosynthesis. 21-hydroxylase deficiency accounts for the overwhelming majority of cases.

The enzymatic block shunts steroid precursors towards androgen synthesis. The result is glucocorticoid deficiency and androgen excess, with mineralocorticoid deficiency in the more severe, classic form.

The classic presentations are salt-wasting adrenal crisis in severely affected infants and virilisation, most apparent in affected female infants. Early diagnosis and treatment of the salt-wasting form is critical and time-sensitive, so newborn screening is now widely implemented in many jurisdictions.

Pathophysiology and classification

• 21-hydroxylase deficiency, from mutations in the CYP21A2 gene, blocks two conversions: 17-hydroxyprogesterone to 11-deoxycortisol (an essential step in cortisol synthesis) and progesterone to deoxycorticosterone (an essential step in aldosterone synthesis).
• The upstream precursors accumulate, particularly 17- hydroxyprogesterone, which is diverted towards the androgen synthesis pathway. This produces excess androgens, together with reduced cortisol and, in the more severe form, reduced aldosterone.
• Classic congenital adrenal hyperplasia has two subtypes:
  • Salt-wasting form: the more severe presentation, with near-complete enzyme deficiency, significant aldosterone and cortisol deficiency, and marked androgen excess.
  • Simple virilising form: sufficient residual enzyme activity maintains adequate mineralocorticoid production despite significant glucocorticoid deficiency and androgen excess.
• Non-classic congenital adrenal hyperplasia is a milder, partial enzyme deficiency. It generally presents later in childhood or adulthood with milder androgen excess symptoms, not the dramatic presentations of the classic forms.
• Less common causes are substantially rarer but belong in the differential diagnosis:
  • 11-beta-hydroxylase deficiency: androgen excess with, characteristically, hypertension rather than salt-wasting, because the mineralocorticoid precursor deoxycorticosterone accumulates.
  • 17-alpha-hydroxylase deficiency: reduced androgen and oestrogen production, producing a distinct clinical phenotype.

• Affected female infants with classic congenital adrenal hyperplasia typically present at birth with virilised (ambiguous) external genitalia. This reflects androgen excess during fetal development. Severity ranges from mild clitoromegaly to genitalia closely resembling a normal male phenotype. It is an important immediate feature that often prompts urgent evaluation in the newborn period.
• Affected male infants with classic disease typically have normal-appearing external genitalia at birth, because androgen excess produces no externally apparent abnormality in an already androgen-exposed male fetus. Diagnosis in affected males therefore relies substantially on newborn screening or on recognising the salt-wasting crisis, not on a physical finding at birth.
• Salt-wasting adrenal crisis reflects combined mineralocorticoid and glucocorticoid deficiency in the severe, classic salt-wasting form. It typically presents within the first one to two weeks of life with poor feeding, vomiting, weight loss and lethargy. If unrecognised, progressive dehydration, hyponatraemia, hyperkalaemia and hypoglycaemia lead to circulatory collapse and shock. It is a life-threatening paediatric emergency needing immediate recognition and treatment.
• Simple virilising congenital adrenal hyperplasia, without significant mineralocorticoid deficiency, causes genital virilisation in affected females, without the salt-wasting crisis.
• In both sexes, untreated simple virilising disease causes progressive signs of androgen excess over childhood:
  • early, rapid growth with advanced bone age, reducing final adult height through premature epiphyseal fusion
  • premature pubic hair development
  • in males, penile enlargement without testicular enlargement (an important distinguishing feature from true, central precocious puberty)
• Non-classic congenital adrenal hyperplasia typically presents later, in childhood or adolescence, with premature pubic hair and accelerated growth. In adolescent and adult women it causes hirsutism, acne, and menstrual irregularity. This milder spectrum can be a diagnostic challenge, because it overlaps with more common causes of hyperandrogenism in this population, including polycystic ovary syndrome.

• Newborn screening measures 17-hydroxyprogesterone on the routine newborn dried blood spot sample, and is widely implemented in many jurisdictions. It identifies affected infants, particularly those with the severe salt-wasting form, before a potentially life-threatening adrenal crisis. It has a relatively high false positive rate, particularly in premature infants, so it needs careful clinical correlation and confirmatory testing.
• Elevated serum 17-hydroxyprogesterone is the key biochemical marker for 21-hydroxylase deficiency. Markedly elevated levels support the diagnosis in a symptomatic infant or after a positive newborn screening result.
• More borderline elevations may need an ACTH stimulation test with measurement of the 17-hydroxyprogesterone response. This is particularly relevant for distinguishing non-classic disease from a false positive screening result or simple heterozygous carrier status.
• Assess electrolytes, glucose, and clinical status in any newborn with suspected or confirmed congenital adrenal hyperplasia, to identify and promptly treat any evolving salt-wasting crisis.
• Genetic testing for CYP21A2 mutations gives definitive molecular confirmation. It supports genetic counselling on recurrence risk in future pregnancies, given the autosomal recessive inheritance.
• Karyotype is essential in any infant with ambiguous genitalia, following the broader principles for disorders of sexual development. It confirms genetic sex, because virilised female infants with congenital adrenal hyperplasia may otherwise be mistaken for males on external genital appearance alone. It also supports evaluation and family counselling.

• Emergency management of a salt-wasting adrenal crisis is a paediatric emergency needing prompt, aggressive treatment:
  • intravenous fluid resuscitation with isotonic saline
  • intravenous hydrocortisone, given for glucocorticoid replacement and, at higher doses, for its inherent mineralocorticoid activity, which gives temporary mineralocorticoid support until fludrocortisone is established
  • correction of any associated hypoglycaemia and hyperkalaemia
• Long-term management is glucocorticoid replacement with hydrocortisone. The dose both replaces the deficiency and suppresses the excess adrenocorticotropic hormone drive responsible for ongoing androgen excess.
• Titrate the dose carefully to achieve adequate androgen suppression while avoiding the growth-suppressing and other adverse effects of excessive glucocorticoid. This is a challenging, ongoing balance needing structured monitoring.
• For the salt-wasting form, add mineralocorticoid replacement with fludrocortisone.
• Educate the patient and family on sick day dose adjustment, which means increasing the glucocorticoid dose during intercurrent illness or other physiological stress, on broadly similar principles to adrenal insufficiency generally. This is essential, given the life-threatening risk of adrenal crisis during physiological stress.
• Ensure emergency parenteral hydrocortisone is available for severe illness, vomiting, or inability to tolerate oral medication. Provide a medical alert bracelet or card.
• Structured monitoring throughout childhood includes:
  • clinical assessment (growth, pubertal development, and blood pressure)
  • biochemical monitoring of 17-hydroxyprogesterone and androstenedione, to assess androgen suppression and guide glucocorticoid dose titration
  • bone age assessment, to monitor for excessive androgen exposure affecting growth and skeletal maturation
• Genital reconstructive surgery for significantly virilised female infants is an area of substantial, ongoing evolution in practice and ethical consideration. Contemporary approaches increasingly favour a conservative, individualised approach. Irreversible surgery is deferred where possible, and the individual's own future involvement in decisions about elective surgery is incorporated where feasible. This needs careful, sensitive, multidisciplinary discussion with the family.
• Genetic counselling for the family addresses the autosomal recessive inheritance and the recurrence risk in future pregnancies. Where relevant, discuss prenatal diagnosis and, in highly selected circumstances under specialist guidance, prenatal treatment for a subsequent at-risk pregnancy.
• Plan structured transition to adult endocrinology services, because the condition is lifelong and its management extends well beyond childhood.