Congenital Adrenal Hyperplasia

The incidence of 21-OHD CAH is one in 14,000 to 18,000 newborns, according to a literature review encompassing 20 countries.[6,8] The incidence of classic CAH seems to be greater in Caucasian and Asian babies than in Hispanic and African American infants. Because of the variability in symptoms and incomplete data reporting, the incidence in nonclassic CAH is less well supported, but it seems closer to 1 in 1,000 newborns.[4,9]

The most common cause of CAH is 21-hydroxylase deficiency, the result of one of at least 10 mutations in the 21-hydroxylase-encoding gene CYP21A2 located on chromosome 6p21.33.[1,4,6] 21-Hydroxylase is essential to converting progesterone to aldosterone and 17-OH progesterone to cortisol.[6] 

The hypothalamic-pituitary-adrenal axis is responsible for regulating the adrenal cortex’s secretion of cortisol. In the absence of adequate cortisol levels, the hypothalmus and pituitary gland are prompted to compensate, overproducing corticotropin-releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH). That positive feedback loop causes an abnormal enlargement of the adrenal gland and accumulation of cortisol precursors produced by the adrenal gland.[1,4] 

With the inability to convert these precursors to cortisol, the body converts them to androgens instead, resulting in excess androgen concentrations.[3] High androgen levels prenatally result in abnormal development of external genitalia in females (“virilization”).[6] 

Patients with 21-OHD have a concomitant issue—impaired cortisol biosynthesis results in increased 17-hydroxyprogesterone (17-OHP) and progesterone levels. Patients with CYP21A2 mutations that cause complete loss of function will have impaired aldosterone synthesis, a result of poor urinary sodium reabsorption.[4] Aldosterone deficiency is seen in up to 75% of these young patients.[5]

Patients with CAH will generally present with enlarged adrenal glands, which result from the overproduction of androgens. 

In female patients with classic CAH, the excess androgen levels cause abnormal or ambiguous development of the external genitalia, though their internal reproductive organs are not normally affected.[4] In males with classic CAH, external genitalia may not be affected, but they are at risk for poor development of sexual organs (e.g., small testes).[4] 

Untreated patients with 21-OHD may exhibit early onset of puberty, premature pubic hair growth, rapid body growth, and (ironically) short stature arising from premature completion of growth.[4] 

The aldosterone deficiency seen in most patients with CAH can cause life-threatening salt loss, with hyponatremia, hyperkalemia, and acidosis.[1,5]

Other signs in young women with poorly controlled, nonclassic CAH include acne, hirsutism, irregular periods, and male pattern baldness.[6] In males with nonclassic CAH, signs are less overt: ACTH levels are not necessarily increased. Genetic screening, necessitated by a diagnosis within a family, seems to be the most common way of identifying these particular patients.[1,4]

Beyond detecting the pathogenic variant in patients with nonclassic CAH, the key diagnostic sign is an elevation in the concentration of 17-hydroxyprogesterone (> 200 ng/dL). Low or absent 21-hydroxylase is available to enzymatically convert this molecule to cortisol.[1,6] Patients with classic CAH will have levels 500-fold higher than this. In those with slightly abnormal 17-hydroxyprogesterone levels, a cosyntropin stimulation test will be needed to confirm the diagnosis.[1] False-positive tests are frequent, however, based on timing of the blood sample and a patients’ menses cycle. Furthermore, an ACTH stimulation test may also be warranted to complete the diagnosis.[4]

Another rare disorder, pseudohypoaldosteronism, can produce a salt-wasting crisis in neonates, and can be a confounding factor in the differential diagnosis.[10] 

The vast majority of infants in the United States and other developed countries undergo universal newborn screening for CAH caused by 21-hydroxyprogesterone deficiency.[5,6] These screening programs generally test for elevated blood levels of 17-hydroxyprogesterone; however, these have been associated with high false-positive rates, especially in premature and low-birthweight infants.[5] A second newborn screening is mandated by some states, generally within 2 weeks of a positive test result,[4] and another marker (e.g., 21-deoxycortisol) used in the second-tier test has the potential to improve test specificity and sensitivity.[5,11]

In those with nonclassic CAH, newborn screening is less likely to detect the genetic variant. Since symptoms appear later in childhood, and it usually doesn’t pose early symptoms that require treatment, focus on signs such as excess facial or body hair, or acne development may be a tip-off to the diagnosis. If unrevealed until later in life, nonclassic CAH may be misdiagnosed as polycystic ovarian syndrome, because of their similar presentations of irregular menses, hirsutism, and infertility.[9]

Adrenal crisis and salt-wasting crisis are the most dangerous complications of CAH. Glucocorticoid replacement therapy can be life-saving, but long-term glucocorticoid treatment has a multitude of well-known adverse effects, including weight gain, diabetes, cardiovascular issues, short stature, and bone loss. In a Swedish study, adrenal crisis was the cause of death in 42% of 588 patients with CAH.[6] Adrenal crises have been recorded to occur at a rate of 5–10 crises/100 patient-years.[6] Patients with classic CAH and their caregivers are encouraged to have easy access to a glucocorticoid injection kit in case of adrenal crisis.[4,9] Overall, patients with CAH survive into adulthood, but their lifespan may be shortened (by 18 years in a British matched cohort study).[6]

Physiologic stressors, such as illness, trauma, and surgery/recovery, are well known to cause adrenal crisis in patients with CAH. A recent survey of 115 parents of 118 children with CAH revealed that psycho-emotional stress may also precipitate adrenal crisis.[12] 

Testicular adrenal rest tumors are the result of ACTH overstimulation of the adrenal tissue. These are treatable but can result in infertility and testicular damage if unmanaged.[13] 

Resulting from CAH-associated issues with genital development, gender dysphoria seems to be a frequent issue, especially in certain children raised as female. Patients with marked virilization, those who received a delayed diagnosis, and individuals with inconsistent adherence to glucocorticoid treatment seemed to be at relatively greater risk for gender dysphoria in one case series of 19 patients.[14] 

Patients’ health-related quality of life are negatively affected by CAH, including ratings of self-esteem, shame, impaired social functioning, among others.[15] 

Generally, upon diagnosis of classic CAH, both glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone acetate) replacement treatments should be instituted.[4,6] The dose of hydrocortisone in infants and older pediatric patients is 6–15 mg/m2/day, in three divided doses. Doses above this range are associated with short stature. Prednisone or dexamethasone can be used as an alternative in adult patients. For patients under stress, such as for significant illness or undergoing surgery, tripling of the steroid dose temporarily (i.e., “stress dosing”) is advised, according to age-based guidelines. Dosing of fludrocortisone acetate is titrated (0.05–0.2 mg/day in children and adults) to attain plasma renin activity that is in the reference range (based on patient age).[4] 

For adolescents and adult women with nonclassic CAH who exhibit signs of hyperandrogenism, such as acne or hirsutism, and irregular menses, oral contraceptive therapy (i.e., estrogen-progestin preparations) is the treatment of choice.[4,9] These medications suppress ovarian androgen production and free androgen concentrations, and increase the body’s clearance of testosterone.[1] Depending on their symptoms, men with nonclassic CAH may not require systemic therapy. 

Recently, research has described some new mechanisms that may offer alternative therapeutic pathways, allowing for lower corticosteroid dosing.[7,16] For example, corticotropin-releasing factor type 1 receptor antagonism seems to control excess ACTH and adrenal androgen production, and it is independent of glucocorticoid production. An investigational oral CRF-1 antagonist, crinecerfont, has undergone randomized and controlled phase 3 clinical studies in pediatric patients and adults with classic CAH, demonstrating lower androstenedione levels over a 28-week treatment period, with significant decreases in concomitant glucocorticoid doses needed.[17] Headache, pyrexia, and vomiting were the most common side effects noted in young patients,[17] whereas fatigue and headache were the main adverse effects in adults.[18]

Go to www.clinicaltrials.gov to find studies that are actively recruiting patients with CAH.

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Living With CAH

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1. Jha S, Turcu AF. Non-classic congenital adrenal hyperplasia: What do endocrinologists need to know? Endocrinol Metab Clin North Am. 2021;50:151–165. https://doi.org/10.1016/j.ecl.2020.10.008.
2. Bouliari A, Lekarev O, Lin-Su K. Update in adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2026;55:201-222. https://doi.org/10.1016/j.ecl.2026.01.001.
3. Kluge ML, Schema L, Schroepfer K, et al. 21-Hydroxylase deficient congenital adrenal hyperplasia due to maternal uniparental isodisomy. Case Rep Endocrinol. 2026;2026:3596318. https://doi.org/10.1155/crie/3596318.
4. Witchel SF. Congenital adrenal hyperplasia. J Pediatr Adolesc Gynecol. 2017;30:520-534. https://doi.org/10.1016/j.jpag.2017.04.001.
5. Miller WL. Congenital adrenal hyperplasia: Time to replace 17OHP with 21-deoxycortisol. Horm Res Paediatr. 2019;91:416–420. https://doi.org/10.1159/000501396.
6. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrendal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocrine Rev. 2022;43:91-159. https://doi.org/10.1210/endrev/bnab016.
7. Graves LE, Falhammar H. Advances in pharmacological treatment for congenital adrenal hyperplasia. Curr Opin Pediatr. 2026 May 26. https://doi.org/10.1097/MOP.0000000000001583. (Online ahead of print).
8. Fanis P, Skordis N, Tomazou M, et al. Congenital adrenal hyperplasia in the Mediterranean: A concise overview. Pharmaceuticals (Basel). 2026;19:741. https://doi.org/10.3390/ph19050741.
9. Ferral K. Different types of congenital adrenal hyperplasia (CAH)—classic vs. nonclassic. Mayo Clinic July 9, 2024. https://mcpress.mayoclinic.org/cah/different-types-of-congenital-adrenal-hyperplasia-cah-classic-vs-nonclassic/?utm_source=google_search&utm_medium=cpc&utm_campaign=mc_cs_ag_167722027670&utm_content=mc_cs_cid_{adid}&gad_source=1&gad_campaignid=21410153936&gbraid=0AAAAADzi-Vjkm4cC6E6th_TQryb0RGvFK&gclid=Cj0KCQjwi8nRBhDhARIsAHZf_pY82izIKpWcdTcxNTPMGj1iyWlcCmWrAvD8NKnZkxqh_-FWfq5JxDsaAoV1EALw_wcB. Accessed June 15, 2026. 
10. Abdulsalam TA(1), Obaisi TA. A neonatal salt-wasting crisis mimicking congenital adrenal hyperplasia: A case of transient pseudohypoaldosteronism. Cureus. 2026;18:e107777. https://doi.org/10.7759/cureus.107777.
11. de Hora M, Heather N, Webster D, et al. 21-Deoxycortisone: A novel sensitive and specific newborn screening marker for congenital adrenal hyperplasia. Int J Neonatal Screen. 2026; 12:27. https://doi.org/10.3390/ijns12020027.
12. Cubberley SK, Minns LA. Parent-perceived stressors and stress-dosing practices during suspected adrenal crisis in children with congenital adrenal hyperplasia: a cross-sectional, parent-reported study. J Pediatr Endocrinol Metab. 2026 May 15. https://doi.org/10.1515/jpem-2025-0604. Online ahead of print.
13. Sahu P, Agarwal P, Sai V, et al. Imaging spectrum and surveillance of testicular adrenal rest tumours in congenital adrenal hyperplasia: A case series. Cureus. 2026;18:e108383. https://doi.org/10.7759/cureus.108383.
14. Barroso IA, Marimpietri FS, Ribeiro GM, et al. Gender dysphoria in congenital adrenal hyperplasia: A review of the cases described in the literature. J Pediatr Urol. 2026;22:105960. https://doi.org/10.1016/j.jpurol.2026.105960. Online ahead of print.
15. James KL, Parkin N, Elford S, et al. Factors affecting the quality of life of adults living with congenital adrenal hyperplasia: a qualitative study of lived experience. Endocr Connect. 2026;15:e260033. https://doi.org/10.1530/EC-26-0033.
16. Nokoff NJ, Fechner PY, Kim MS, et al. Glucocorticoid reduction after starting crinecerfont in pediatric patients with classic CAH: Practical perspectives. J Clin Endocrinol Metab. 2026 May 4:dgag192. https://doi.org/10.1210/clinem/dgag192. Online ahead of print.
17. Sarafoglou K, Kim MS, Lodish M, et al. Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia. N Engl J Med. 2024;391:493-503. https://doi.org/10.1056/NEJMoa2404655.
18. Auchus RJ, Hamidi O, Pivonello R, et al. Phase 3 trial of crinecerfont in adult congenital adrenal hyperplasia. N Engl J Med. 2024;391:504-514. https://doi.org/10.1056/NEJMoa2404656.