Congenital Adrenal Hyperplasia · CAH

Description

Congenital adrenal hyperplasia, CAH, in its classic form is an autosomal recessive disorder of adrenal steroid synthesis. More than 95 percent of cases are caused by 21-hydroxylase deficiency. Pathogenic variants in CYP21A2 reduce or abolish 21-hydroxylase activity in the adrenal cortex. The block impairs cortisol synthesis and, in the salt-wasting form, aldosterone synthesis. Loss of cortisol-mediated negative feedback raises adrenocorticotropic hormone, which drives adrenal hyperplasia and shunts steroid precursors into the androgen pathway. Inheritance is autosomal recessive. The causative gene is CYP21A2 on chromosome 6.

Classic CAH has two clinical forms. Salt-wasting disease, roughly two-thirds of classic cases, presents in the first two to three weeks of life with vomiting, poor feeding, weight loss, hyponatremia, hyperkalemia, and adrenal crisis. Simple-virilizing disease retains enough aldosterone activity to avoid salt wasting and presents with prenatal androgen excess. Genetic females with classic CAH are typically born with virilized external genitalia. Genetic males appear unremarkable at birth, which historically delayed diagnosis until salt-wasting crisis or, in simple-virilizing disease, until early virilization.

Detection is by newborn screening on the dried blood spot, measuring 17-hydroxyprogesterone by immunoassay, often followed by tandem mass spectrometry as a second tier to reduce false positives. Confirmation uses serum 17-hydroxyprogesterone, electrolytes, plasma renin activity, and CYP21A2 gene sequencing.

Reported worldwide birth incidence of classic 21-hydroxylase deficiency is approximately 1 in 14,000 to 1 in 18,000, summarized in the Endocrine Society clinical practice guideline by Speiser et al. (Journal of Clinical Endocrinology and Metabolism, 2018). Yup'ik people of southwestern Alaska have a documented founder effect, with reported incidence near 1 in 280 births.

Non-classic CAH, with milder enzyme deficiency, presents later in childhood or adulthood with signs of androgen excess and is managed separately.

Treatments to date

Treatment begins as soon as classic CAH is suspected after newborn screening or clinical presentation, and continues for life. Goals are to replace deficient cortisol, replace aldosterone in salt-wasting disease, suppress excess adrenal androgens, support normal growth and puberty, and prevent adrenal crisis.

Glucocorticoid replacement is the foundation of care. Hydrocortisone is the standard glucocorticoid in childhood because longer-acting steroids impair growth. Doses are individualized and adjusted with growth, puberty, and laboratory monitoring. Mineralocorticoid replacement with fludrocortisone, often supplemented with oral sodium chloride in infancy, is added in salt-wasting disease.

Stress dosing is lifelong. During febrile illness, vomiting, surgery, or trauma, oral or parenteral hydrocortisone is increased to prevent adrenal crisis. Families and adults with CAH carry emergency injectable hydrocortisone and a written stress-dose plan.

Crinecerfont, marketed as Crenessity, was approved by the FDA in December 2024 as adjunctive therapy in adults and in children four years and older with classic CAH. It is a corticotropin-releasing factor type 1 receptor antagonist taken orally. By reducing pituitary adrenocorticotropic hormone secretion, it lowers adrenal androgen output and supports glucocorticoid dose reduction toward more physiologic levels, an effect demonstrated in the CAHtalyst program.

Surgical management of virilized external genitalia in genetic females is individualized, with growing emphasis on shared decision-making and on deferring elective procedures when feasible. Fertility, bone health, metabolic health, and mental health are tracked across the lifespan.

No approved gene therapy exists for CAH. Investigational programs include AAV-delivered CYP21A2 gene therapy currently in early-phase trials.