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" 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).
- 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.
- Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 1995; 80:2322.
- 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.
- 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.
- 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.