Congenital Lipoid Adrenal Hyperplasia

Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal hyperplasia, with failure of synthesis of all adrenal and gonadal steroids. It is autosomal recessive and is caused by variants in STAR, or less often CYP11A1.

It is rare worldwide, but more frequent in Japanese, Korean and Palestinian populations because of founder variants. Salt wasting presents in the first weeks of life in most patients.

46,XY infants have female external genitalia, and 46,XX infants have normal female genitalia. Non-classic forms with later onset are described, mainly with partial STAR or CYP11A1 activity.

Pathophysiology.

STAR moves cholesterol into mitochondria, the first step in steroid synthesis. Its loss causes adrenal cells to fill with cholesterol esters, which damages them, so adrenal enlargement is lipid laden.

In 46,XX patients the ovary is spared until puberty, when follicles make some oestradiol and spontaneous puberty can occur, followed by ovarian failure. Testes are damaged early.

• Neonatal salt wasting crisis: vomiting, poor feeding, dehydration, hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia.
• 46,XY: female external genitalia with a blind ending vagina and inguinal or abdominal testes. 46,XX: normal genitalia, delayed or arrested puberty with later ovarian failure.
• Skin hyperpigmentation from raised ACTH.

Red flags.

• Neonatal collapse with hyponatraemia and hyperkalaemia.
• Female phenotype with undescended testes (malignancy risk).

• All steroids low or undetectable (cortisol, aldosterone, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone sulphate), with very high ACTH and renin. No steroid response to ACTH.
• Electrolytes: sodium low, potassium high, glucose low.
• Ultrasound or MRI: enlarged adrenal glands with lipid rich content. Karyotype and pelvic imaging.
• STAR and CYP11A1 sequencing confirms the diagnosis and allows family testing.

Differential diagnosis.

• 3-beta hydroxysteroid dehydrogenase deficiency, 21-hydroxylase deficiency and 17-alpha hydroxylase deficiency (specific steroid precursors are raised).
• Adrenal haemorrhage, adrenal hypoplasia congenita (small glands, NR0B1) and familial glucocorticoid deficiency.
• Complete androgen insensitivity syndrome and Smith-Lemli-Opitz syndrome.
• Sepsis, urinary tract obstruction and other causes of neonatal salt loss.

• Acute crisis: intravenous 0.9% sodium chloride 20 mL/kg as a bolus, hydrocortisone 50 to 100 mg/m2 (100 mg in adults), 10% glucose 2 to 5 mL/kg for hypoglycaemia, and potassium monitoring.
• Maintenance: hydrocortisone 10 to 15 mg/m2 daily in three divided doses in children (adults 15 to 25 mg daily in two or three divided doses), fludrocortisone 0.05 to 0.2 mg daily, and sodium chloride 1 to 2 g daily in infants.
• Stress dosing: double or triple the dose for fever and illness, and give hydrocortisone 100 mg intramuscularly or intravenously for vomiting or collapse (children 50 to 100 mg/m2). Teach the family to give the injection.
• Sex steroid replacement at the age of puberty, chosen by the sex of rearing: oestradiol (for example 0.25 mg orally daily, increased gradually to 2 mg daily) with a progestogen once breakthrough bleeding occurs or after 2 years; testosterone for those raised male.
• Gonadectomy for 46,XY patients raised female. Specialist team for gender and psychological support.

Special groups. Fertility: 46,XX women can ovulate in early adult life and may need ovarian reserve review and assisted reproduction. Genetic counselling: 25% recurrence risk in siblings.

Monitoring. Children every 3 to 4 months: growth, blood pressure, sodium, potassium, renin, ACTH. Bone age yearly, bone density in adults.

Referral and escalation. Paediatric endocrinology and a specialist disorders of sex development team; emergency admission for adrenal crisis.