The packet lists CYP21A2 (chromosome 6) as the associated gene, with autosomal recessive inheritance.

GeneReviews states that the classic form is predicted to involve severe pathogenic variants on both CYP21A2 alleles, with completely abolished enzyme activity in in vitro expression studies, whereas the non-classic form is predicted to involve two mild variants or one mild and one severe variant. Salt-wasting disease usually involves the most severe variants (for example, homozygous deletions). A direct genotype-phenotype correlation was found in approximately 50% of genotypes in the largest cohort, with the least reliable predictions in the simple virilizing form.

According to GeneReviews, most parents of a proband are carriers of one CYP21A2 pathogenic variant, and approximately 1% of pathogenic variants occur de novo. Carriers are described as asymptomatic but may show slightly elevated 17-hydroxyprogesterone after ACTH stimulation. When both parents are carriers, GeneReviews gives each sibling a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

GeneReviews describes suspicion of 21-OHD CAH in females virilized at birth or postnatally, in males with childhood masculinization, in any infant with a salt-losing crisis in the first four weeks of life, and in an infant with elevated 17-hydroxyprogesterone on newborn screening. Affected females and males have normal 46,XX and 46,XY karyotypes, respectively.

GeneReviews states that newborn screening aims to identify infants, especially males, with the classic form who are at risk for life-threatening salt-wasting crises and to expedite diagnosis of females with ambiguous genitalia. It measures 17-hydroxyprogesterone on a heel-stick blood spot and rarely detects the non-classic form. GeneReviews notes that samples taken in the first 24 hours of life, and those from low birth-weight or premature infants, can give false-positive results. The packet does not certify newborn-screening panel status for this condition.

Per GeneReviews, the diagnosis in a newborn is established by markedly elevated serum 17-hydroxyprogesterone, elevated adrenal androgens, markedly elevated plasma renin activity in the salt-wasting form (with aldosterone inappropriately low relative to renin activity), and identification of biallelic CYP21A2 pathogenic variants.

The packet does not certify any FDA-approved treatment records or foundational-therapy fields for this condition; the description below is drawn from the GeneReviews management section.

GeneReviews describes a multidisciplinary team of pediatric endocrinology, pediatric urology or surgery, clinical genetics, and psychology as essential for individuals with ambiguous genitalia, and notes that two CAH comprehensive care centers have been designated in the United States. For classic 21-OHD CAH, glucocorticoid replacement is described as the principal treatment, with goals of replacing deficient steroids, minimizing adrenal sex hormone and glucocorticoid excess, preventing virilization, optimizing growth, and promoting fertility. Hydrocortisone tablets are described as the treatment of choice in growing children; overtreatment is noted to cause cushingoid features. GeneReviews states that physical stress such as surgery, febrile illness, or major trauma can precipitate adrenal crisis, that increased glucocorticoid amounts are used in these situations, and that glucocorticoid administration is lifelong. Mineralocorticoid replacement with fludrocortisone and sodium chloride is described for the salt-wasting form and for infants with the classic form. GeneReviews also describes feminizing genitoplasty, citing a 2006 consensus statement that surgery be considered only in severe virilization (Prader III-V), with emphasis on functional outcome.

For surveillance, GeneReviews describes assessing glucocorticoid therapy through early-morning 17-hydroxyprogesterone, 4-androstenedione, and testosterone, growth, pubertal development, and bone age, and mineralocorticoid therapy through blood pressure and plasma renin activity, about every three to four months in actively growing children and less often thereafter. GeneReviews labels prenatal maternal dexamethasone, growth hormone with or without GnRH, and aromatase inhibitors as experimental approaches to be used only within formal clinical trials.

The packet does not include a certified natural-history field or survival information for this condition. GeneReviews describes salt-wasting crises as life-threatening in newborns with the salt-wasting form, and the packet definition notes that neonatal dehydration and hypoglycemia can be lethal if untreated. GeneReviews also states that individuals do not generally achieve the expected adult height even with early treatment, that overall fertility rates are reported to be low, and that prediction of phenotype from genotype is imperfect. Beyond these descriptions, prognosis is not certified in this packet.

The packet lists numerous clinical trial records on ClinicalTrials.gov associated with this condition, with intervention types including drug therapy, other interventions, medical devices, and gene therapy. Records naming congenital adrenal hyperplasia include NCT07144163, a Phase 3 study titled as evaluating atumelnant in adults (Crinetics Pharmaceuticals, recruiting); NCT07159841, a Phase 2 pediatric study (Crinetics, recruiting); NCT07187375 and NCT07536269, Phase 2 studies titled as examining crinecerfont in participants under 2 and under 4 years of age (Neurocrine Switzerland GmbH; active not recruiting and recruiting); and NCT07850739, a Phase 2 study in adults with classic CAH (Neurocrine Biosciences; not yet recruiting). A trial title does not by itself establish the intervention, and listing does not imply efficacy or approval.