Familial Glucocorticoid Deficiency

Familial glucocorticoid deficiency is an autosomal recessive form of primary adrenal insufficiency with cortisol deficiency, high ACTH and preserved mineralocorticoid function.

It is rare. About 25% of cases are due to variants in the ACTH receptor (MC2R, type 1) and about 20% to its accessory protein (MRAP, type 2). Other genes are NNT, TXNRD2, STAR, CYP11A1, MCM4 and GPX1.

It presents in the neonatal period with hypoglycaemia and jaundice, or in childhood with recurrent infection, hypoglycaemic seizures or collapse. Tall stature is common in MC2R disease.

Pathophysiology.

The adrenal cortex cannot respond to ACTH, so cortisol is low and ACTH high, which causes hyperpigmentation. The zona glomerulosa is spared because aldosterone is controlled by the renin angiotensin system.

Oxidative stress genes (NNT, TXNRD2) cause cortisol deficiency through mitochondrial injury, and may also cause mild mineralocorticoid deficiency.

• Hypoglycaemia with seizures, neonatal jaundice and failure to thrive, recurrent infections (sometimes fatal in infancy).
• Hyperpigmentation of skin and gums, fatigue, vomiting and tall stature in MC2R disease. Normal puberty in most.
• Adrenal crisis during infection.

Red flags.

• Hypoglycaemic seizure, shock or sudden infant death in a family member.
• Hyperpigmentation with unexplained hypoglycaemia in a child.

• Morning cortisol low (under 100 nmol/L confirms deficiency) with ACTH very high, and no cortisol rise to short tetracosactide 250 micrograms (peak under about 450 nmol/L). Glucose low during illness.
• Normal sodium, potassium, renin and aldosterone in most patients. Adrenal androgens and DHEAS are low.
• Exclude adrenal autoimmunity (adrenal antibodies negative), adrenoleukodystrophy (very long chain fatty acids) and congenital adrenal hyperplasia (17-hydroxyprogesterone, androgens).
• Genetic testing of MC2R, MRAP, NNT, TXNRD2, STAR, CYP11A1 and MCM4. Adrenal imaging is not needed.

Differential diagnosis.

• Congenital adrenal hyperplasia and congenital adrenal hypoplasia (NR0B1).
• Adrenoleukodystrophy, triple A syndrome (Allgrove syndrome) and autoimmune adrenalitis.
• Secondary adrenal insufficiency with low ACTH, and neonatal sepsis.

• Hydrocortisone 10 to 15 mg/m2 daily in three divided doses, adjusted to growth, weight, ACTH and glucose.
• Illness: double or triple the dose for fever or illness, and 50 to 100 mg/m2 intramuscularly or intravenously for crisis or vomiting, with dextrose and fluids (0.9% sodium chloride 20 mL/kg).
• Fludrocortisone 0.05 to 0.2 mg daily if there is mineralocorticoid deficiency (NNT, TXNRD2 or STAR variants).
• Teach parents emergency injection, give a steroid card and medical alert identification.
• Genetic counselling: 25% recurrence risk in siblings. Prenatal testing is possible when the variant is known.

Special groups. Neonates: hypoglycaemia must be treated without delay (10% glucose 2 mL/kg). Adults: moved to adult care with a hydrocortisone dose of 15 to 25 mg daily in two or three divided doses.

Monitoring. Growth, weight, blood pressure, glucose, ACTH and electrolytes every 3 to 6 months. Avoid over replacement, which causes weight gain and growth suppression.

Referral and escalation. Paediatric endocrinology; emergency admission for crisis.