Highlights & Basics
- Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders responsible for defects in adrenal steroidogenesis and resulting in diminished cortisol production. The leading enzyme deficiency is 21-hydroxylase (P450c21) and results from a mutation in the CYP21A2 gene. This review will focus on CAH resulting from 21-hydroxylase deficiency, with the other causes reviewed in brief.
- A deficiency in 21-hydroxylase should be considered in an infant with ambiguous genitalia or a child or adolescent with postnatal virilization. Adrenal crisis with biochemical evidence of salt-wasting may occur if this is not promptly diagnosed and historically has been more common in 46,XY individuals with CAH given lack of genital differences at birth. This can also present later in childhood and should be considered with presentations of premature adrenarche, precocious puberty, irregular menses and hirsutism.
- A deficiency of 21-hydroxylase is confirmed by biochemical findings, such as an unequivocally elevated serum concentration of 17-hydroxyprogesterone or follow-up stimulation testing in the case of borderline elevation.
- Classical CAH requires lifelong treatment with glucocorticoid replacement therapy and nonclassical CAH requires treatment only in select symptomatic patients.
Quick Reference
History & Exam
Key Factors
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Diagnostics Tests
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Definition
Epidemiology
Etiology
Pathophysiology
Images
Gene map of two homologs: CYP21A2 (the active gene) and CYP21A1P (the pseudogene). Noncorrespondent bases number less than 90 over a distance of 5.1 kb of DNA. Numbered are the pseudogene base changes that are frequently identified on mutant CYP21A2 genes responsible for 21OHD. Mutations associated with NC21OHD are indicated with black squares (exons 1, 7, 8, and 10)
Scheme of adrenal corticosteroid synthesis
Skin before and after treatment with dexamethasone for 3 months
Male-pattern baldness typical of females affected with nonclassical 21-hydroxylase deficiency
Prader Score: degree of virilization of the external genitalia of females as proposed by Prader. In type I, the only abnormality is a slight enlargement of the clitoris. In type V, there is a markedly enlarged phallus with a penile urethra
Nomogram relating baseline to ACTH-stimulated serum concentrations of 17-hydroxyprogesterone. The scales are on log^10. A regression line for all data points is shown
Citations
White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000 Jun;21(3):245-91.[Abstract][Full Text]
Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020 Sep 24;383(13):1248-61.[Abstract]
Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia-current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022 Jan 12;43(1):91-159.[Abstract][Full Text]
Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018 Nov 1;103(11):4043-88. [Abstract][Full Text]
1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000 Jun;21(3):245-91.[Abstract][Full Text]
2. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020 Sep 24;383(13):1248-61.[Abstract]
3. Auer MK, Nordenström A, Lajic S, et al. Congenital adrenal hyperplasia. Lancet. 2023 Jan 21;401(10372):227-44.[Abstract]
4. Navarro-Zambrana AN, Sheets LR. Ethnic and national differences in congenital adrenal hyperplasia incidence: a systematic review and meta-analysis. Horm Res Paediatr. 2023;96(3):249-58.[Abstract][Full Text]
5. Pearce M, DeMartino L, McMahon R, et al. Newborn screening for congenital adrenal hyperplasia in New York State. Mol Genet Metab Rep. 2016 Mar 12;7:1-7.[Abstract][Full Text]
6. Khattab A, Haider S, Kumar A, et al. Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Proc Natl Acad Sci U S A 2017. 114(10):E1933-40. [Abstract][Full Text]
7. Wilson RC, Wei JQ, Cheng KC, et al. Rapid deoxyribonucleic acid analysis by allele-specific polymerase chain reaction for detection of mutations in the steroid 21-hydroxylase gene. J Clin Endocrinol Metab. 1995 May;80(5):1635-40.[Abstract]
8. Pignatelli D, Carvalho BL, Palmeiro A, et al. The complexities in genotyping of congenital adrenal hyperplasia: 21-hydroxylase deficiency. Front Endocrinol (Lausanne). 2019 Jul 4:10:432.[Abstract][Full Text]
9. New MI, Abraham M, Gonzalez B, et al. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2611-6.[Abstract][Full Text]
10. Finkielstain GP, Chen W, Mehta SP, et al. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2011 Jan;96(1):E161-72.[Abstract]
11. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia-current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022 Jan 12;43(1):91-159.[Abstract][Full Text]
12. Ma D, Yuan Y, Luo C, et al. Noninvasive prenatal diagnosis of 21-Hydroxylase deficiency using target capture sequencing of maternal plasma DNA. Sci Rep. 2017 Aug 7;7(1):7427.[Abstract][Full Text]
13. New MI, Dupont B, Grumbach K, et.al. Congenital adrenal. hyperplasia and related conditions. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, et al., eds. The metabolic basis of inherited disease. 5th ed. New York, NY: McGraw-Hill; 1983:973-1000.
14. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018 Nov 1;103(11):4043-88. [Abstract][Full Text]
15. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab. 1983 Aug;57(2):320-6.[Abstract]
16. Mooij CF, Parajes S, Pijnenburg-Kleizen KJ, et al. Influence of 17-hydroxyprogesterone, progesterone and sex steroids on mineralocorticoid receptor transactivation in congenital adrenal hyperplasia. Horm Res Paediatr. 2015 Apr 15.[Abstract]
17. American College of Medical Genetics and Genomics. Five things physicians and patients should question. Choosing Wisely, an initiative of the ABIM Foundation. 2021 [internet publication]. [Full Text]
18. New MI, Gertner JM, Speiser PW, et al. Growth and final height in congenital adrenal hyperplasia (classical 21-hydroxylase deficiency) and in nonclassical 21-hydroxylase deficiency. In: Cavallo L, Job JC, New MI, eds. Growth disorders: the state of the art, Vol 81. New York, NY: Raven Press; 1991:105-110.
19. Wasniewska MG, Morabito LA, Baronio F, et al; Adrenal Diseases Working Group of the Italian Society for Pediatric Endocrinology and Diabetology. Growth trajectory and adult height in children with nonclassical congenital adrenal hyperplasia. Horm Res Paediatr. 2020;93(3):173-81.[Abstract][Full Text]
20. Prader A. Genital findings in the female pseudo-hermaphroditism of the congenital adrenogenital syndrome; morphology, frequency, development and heredity of the different genital forms [in German]. Helv Paediat Acta. 1954;9:231-248.[Abstract]
21. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440-1447.[Abstract]
22. Gidlöf S, Wedell A, Guthenberg C, et al. Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population-based study. JAMA Pediatr. 2014 Jun;168(6):567-74.[Abstract]
23. Allen DB, Hoffman GL, Fitzpatrick P, et al. Improved precision of newborn screening for congenital adrenal hyperplasia using weight-adjusted criteria for 17-hydroxyprogesterone levels. J Pediatr. 1997 Jan;130(1):128-33.[Abstract]
24. Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics. 1998 Apr;101(4 Pt 1):583-90.[Abstract]
25. Al Saedi S, Dean H, Dent W, et al. Screening for congenital adrenal hyperplasia: the Delfia Screening Test overestimates serum 17-hydroxyprogesterone in preterm infants. Pediatrics. 1996 Jan;97(1):100-2.[Abstract]
26. Rohrer TR, Gassmann KF, Pavel ME, et al. Pitfall of newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Biol Neonate. 2003;83(1):65-8.[Abstract]
27. Saroufim R, Nebesio TD, Eugster EA. Characteristics of patients with classic congenital adrenal hyperplasia missed on the newborn screen. Horm Res Paediatr. 2024;97(5):470-6.[Abstract][Full Text]
28. Screening and management of the hyperandrogenic adolescent: ACOG committee opinion, number 789. Obstet Gynecol. 2019 Oct;134(4):e106-14.[Abstract][Full Text]
29. Baumgartner-Parzer S, Witsch-Baumgartner M, Hoeppner W. EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency. Eur J Hum Genet. 2020 Oct;28(10):1341-67.[Abstract][Full Text]
30. Auchus RJ, Hamidi O, Pivonello R, et al. Phase 3 trial of crinecerfont in adult congenital adrenal hyperplasia. N Engl J Med. 2024 Aug 8;391(6):504-14.[Abstract][Full Text]
31. Van't Westeinde A, Karlsson L, Messina V, et al. An update on the long-term outcomes of prenatal dexamethasone treatment in congenital adrenal hyperplasia. Endocr Connect. 2023 Mar 15;12(4):e220400.[Abstract][Full Text]
32. Brosnan PG, Brosnan CA, Kemp SF, et al. Effect of newborn screening for congenital adrenal hyperplasia. Arch Pediatr Adolesc Med. 1999 Dec;153(12):1272-8.[Abstract]
33. Falhammar H, Frisén L, Norrby C, et al. Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014 Dec;99(12):E2715-21.[Abstract][Full Text]
34. Babu R, Shah U. Gender identity disorder (GID) in adolescents and adults with differences of sex development (DSD): a systematic review and meta-analysis. J Pediatr Urol. 2021 Feb;17(1):39-47.[Abstract]
35. Lin-Su K, Vogiatzi MG, Marshall I, et al. Treatment with growth hormone and luteinizing hormone releasing hormone analog improves final adult height in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2005 Jun;90(6):3318-25.[Abstract]
36. Quintos JB, Vogiatzi MG, Harbison MD, et al. Growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog therapy to improve the height deficit in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001 Apr;86(4):1511-7.[Abstract][Full Text]
37. Wicker LS, Miller BJ, Chai A, et al. Expression of genetically determined diabetes and insulitis in the nonobese diabetic (NOD) mouse at the level of bone marrow-derived cells. Transfer of diabetes and insulitis to nondiabetic (NOD X B10) F1 mice with bone marrow cells from NOD mice. J Exp Med. 1988 Jun 1;167(6):1801-10.[Abstract][Full Text]
38. Ogilvie CM, Crouch NS, Rumsby G, et al. Congenital adrenal hyperplasia in adults: a review of medical, surgical and psychological issues. Clin Endocrinol. 2006;64:2-11.[Abstract]
39. Greulich W, Pyle S. Radiographic atlas of skelatal development of the hand and wrist. 2nd ed. Stanford, CA: Stanford University Press; 1999.
40. S L, Krishna Prasad H, Ramjee B, et al. Audit of management of children and adolescents with congenital adrenal hyperplasia as per recent Endocrine Society guidelines. Pediatr Endocrinol Diabetes Metab. 2023;29(1):10-5.[Abstract][Full Text]
