Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency
- Lynnette K Nieman, MD
Lynnette K Nieman, MD
- Section Editor — Adrenal Disease
- Senior Investigator
- Bethesda, MD
- Deborah P Merke, MD, MS
Deborah P Merke, MD, MS
- Pediatric Endocrinologist
- Bethesda, MD
Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol accounts for more than 90 percent of cases of congenital adrenal hyperplasia (CAH) [1-3]. This conversion is mediated by 21-hydroxylase and is defective due to mutations in the CYP21A2 gene.
The diagnosis and treatment of nonclassic CAH (NCCAH) due to 21-hydroxylase deficiency are reviewed here. The genetics and clinical manifestations of the nonclassic form of 21-hydroxylase deficiency and the classic form of 21-hydroxylase deficiency are reviewed separately. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)
Congenital adrenal hyperplasias (CAHs) are autosomal recessive disorders; 21-hydroxylase deficiency due to mutations in the CYP21A2 gene accounts for approximately 95 percent of cases.
●The most severely affected individuals with classic CAH due to 21-hydroxylase deficiency present during the neonatal period and early infancy with adrenal insufficiency and salt wasting or in the first few years of life with virilization. Females have ambiguous genitalia.
●Most individuals are identified through neonatal screening; the characteristic biochemical abnormality is a high serum concentration of 17-hydroxyprogesterone. Affected neonates have concentrations greater than 3500 ng/dL (105 nmol/L), with most exceeding 10,000 ng/dL (300 nmol/L).To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Witchel SF, Nayak S, Suda-Hartman M, Lee PA. Newborn screening for 21-hydroxylase deficiency: results of CYP21 molecular genetic analysis. J Pediatr 1997; 131:328.
- Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003; 349:776.
- White PC, New MI, Dupont B. Congenital adrenal hyperplasia. (1). N Engl J Med 1987; 316:1519.
- New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983; 57:320.
- White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21:245.
- Azziz R, Dewailly D, Owerbach D. Clinical review 56: Nonclassic adrenal hyperplasia: current concepts. J Clin Endocrinol Metab 1994; 78:810.
- Gutai JP, Kowarski AA, Migeon CJ. The detection of the heterozygous carrier for congenital virilizing adrenal hyperplasia. J Pediatr 1977; 90:924.
- Fiet J, Gueux B, Gourmelen M, et al. Comparison of basal and adrenocorticotropin-stimulated plasma 21-deoxycortisol and 17-hydroxyprogesterone values as biological markers of late-onset adrenal hyperplasia. J Clin Endocrinol Metab 1988; 66:659.
- Bachega TA, Brenlha EM, Billerbeck AE, et al. Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations. J Clin Endocrinol Metab 2002; 87:786.
- Admoni O, Israel S, Lavi I, et al. Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin Endocrinol (Oxf) 2006; 64:645.
- Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013; 98:4565.
- Bonaccorsi AC, Adler I, Figueiredo JG. Male infertility due to congenital adrenal hyperplasia: testicular biopsy findings, hormonal evaluation, and therapeutic results in three patients. Fertil Steril 1987; 47:664.
- Nandagopal R, Sinaii N, Avila NA, et al. Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families. Eur J Endocrinol 2011; 164:977.
- Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrinol Metab 2009; 94:2835.
- Rosenfield RL, Lucky AW. Acne, hirsutism, and alopecia in adolescent girls. Clinical expressions of androgen excess. Endocrinol Metab Clin North Am 1993; 22:507.
- Bidet M, Bellanné-Chantelot C, Galand-Portier MB, et al. Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. J Clin Endocrinol Metab 2009; 94:1570.
- Escobar-Morreale HF, Sanchón R, San Millán JL. A prospective study of the prevalence of nonclassical congenital adrenal hyperplasia among women presenting with hyperandrogenic symptoms and signs. J Clin Endocrinol Metab 2008; 93:527.
- Livadas S, Dracopoulou M, Dastamani A, et al. The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol (Oxf) 2015; 82:543.
- Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 1995; 80:2322.
- Carmina E, Dewailly D, Escobar-Morreale HF, et al. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. Hum Reprod Update 2017; 23:580.
- Ambroziak U, Kępczyńska-Nyk A, Kuryłowicz A, et al. The diagnosis of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, based on serum basal or post-ACTH stimulation 17-hydroxyprogesterone, can lead to false-positive diagnosis. Clin Endocrinol (Oxf) 2016; 84:23.
- Pall M, Azziz R, Beires J, Pignatelli D. The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril 2010; 94:684.
- 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; 96:E161.
- Moran C, Azziz R, Weintrob N, et al. Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia. J Clin Endocrinol Metab 2006; 91:3451.
- Dolzan V, Prezelj J, Vidan-Jeras B, Breskvar K. Adrenal 21-hydroxylase gene mutations in Slovenian hyperandrogenic women: evaluation of corticotrophin stimulation and HLA polymorphisms in screening for carrier status. Eur J Endocrinol 1999; 141:132.
- Glintborg D, Hermann AP, Brusgaard K, et al. Significantly higher adrenocorticotropin-stimulated cortisol and 17-hydroxyprogesterone levels in 337 consecutive, premenopausal, caucasian, hirsute patients compared with healthy controls. J Clin Endocrinol Metab 2005; 90:1347.
- Knochenhauer ES, Cortet-Rudelli C, Cunnigham RD, et al. Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism. J Clin Endocrinol Metab 1997; 82:479.
- Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:4133.
- Joint LWPES/ESPE CAH Working Group.. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 2002; 87:4048.
- Merke DP, Poppas DP. Management of adolescents with congenital adrenal hyperplasia. Lancet Diabetes Endocrinol 2013; 1:341.
- Spritzer P, Billaud L, Thalabard JC, et al. Cyproterone acetate versus hydrocortisone treatment in late-onset adrenal hyperplasia. J Clin Endocrinol Metab 1990; 70:642.
- Frank-Raue K, Junga G, Raue F, et al. [Therapy of hirsutism in females with adrenal enzyme defects of steroid hormone biosynthesis: comparison of dexamethasone with cyproterone acetate]. Klin Wochenschr 1990; 68:597.
- Fern M, Rose DP, Fern EB. Effect of oral contraceptives on plasma androgenic steroids and their precursors. Obstet Gynecol 1978; 51:541.
- Wiebe RH, Morris CV. Effect of an oral contraceptive on adrenal and ovarian androgenic steroids. Obstet Gynecol 1984; 63:12.
- Wild RA, Umstot ES, Andersen RN, Givens JR. Adrenal function in hirsutism. II. Effect of an oral contraceptive. J Clin Endocrinol Metab 1982; 54:676.
- Carr BR, Parker CR Jr, Madden JD, et al. Plasma levels of adrenocorticotropin and cortisol in women receiving oral contraceptive steroid treatment. J Clin Endocrinol Metab 1979; 49:346.
- Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93:1105.
- Birnbaum MD, Rose LI. The partial adrenocortical hydroxylase deficiency syndrome in infertile women. Fertil Steril 1979; 32:536.
- Lo JC, Grumbach MM. Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30:207.
- Speiser PW. Nonclassic adrenal hyperplasia. Rev Endocr Metab Disord 2009; 10:77.
- Casteràs A, De Silva P, Rumsby G, Conway GS. Reassessing fecundity in women with classical congenital adrenal hyperplasia (CAH): normal pregnancy rate but reduced fertility rate. Clin Endocrinol (Oxf) 2009; 70:833.
- Auchus RJ, Arlt W. Approach to the patient: the adult with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2013; 98:2645.
- Horrocks PM, London DR. Effects of long term dexamethasone treatment in adult patients with congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 1987; 27:635.