Diagnosis of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency in Infants and Children - UpToDate

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Diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children  Author: Deborah P Merke, MD, MS Section Editors: Lynnette K Nieman, MD, MD, Mitchell E Geffner, MD Deputy Editor: Kathryn A Martin, MD

 All topics topics are updated as new evidence becomes available and our peer review process is process is complete. Literature review current through: Dec through: Dec 2017. | This topic last updated: Oct updated: Oct 04, 2017. INTRODUCTION — INTRODUCTION — Defective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol accounts for  mor e than 95 percent of cases of congenital adrenal hyperplasia (CAH) [1,2 [1,2]. ]. This conversion conversion is mediated by 21hydr oxylase oxylase due to mutations in the CYP21A2  gene.  gene. Based upon neonatal screening screening studies studies that detect classic CAH, CAH, 21-hydroxylase deficiency (21OHD) is one of the more common inherited disorder s. s. The laboratory findings and diagnosis of classic CAH due to 21OHD in neonates and children are reviewed here. The genetics, clinical presentation, and treatment of classic 21OHD in children and adults and an overview of  nonclassic CAH are discussed d iscussed separately. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and deficiency" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and children" and "Tre "Treat atment ment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults" and adults" and "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".) deficiency".) CLINICAL MANIFESTATION MANIFESTATIONS S — The clinical spectrum of disease ranges from the most severe to mild forms, depending on the the degree of 21-h 21-hydroxylase deficiency deficiency (21OHD). Three main clinical phenotypes have been described: classic salt-losing, classic non-salt-losing (simple virilizing), and nonclassic (late-onset): ●

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Females with the classic form (salt-losing and non-salt-losing) present with genital atypia. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)".) development)".) Males with the salt-losing form who are not identified by neonatal screening present with failure to thrive, dehydration, hyponatremia, hyponatremia, and and hyperkalemia typically at 7 to 14 days of life. Males with the classic non-salt-losing form who are not identified by neonatal screening typically present at two to four years of age with early virilization (pubic hair, growth spurt, adult body od or). Nonclassic or late-onset 21OHD may present as early pubarche or sexual precocity in school-age children, hirsutism and menstrual irregularity in young women, or there may be no symptoms. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".) deficiency" .)

Infants/children Atypical genitalia — genitalia — 46,XX infants with classic 21OHD are born with atypical genitalia characterized by clitoral enlargement (picture (picture 1), 1), labial fusion, and formation of a urogenital sinus caused by the effects of in utero

androgen excess on development of the external genitalia. Rarely, virilization may be so profound that genital atypia is unrecognized, and male sex assignment is made at birth in a 46,XX patient. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)".) development)".)  Affected 46,XY infants are normal appearing at birth but may have subtle findings such as hype rpigmentation of  the scrotum or an enlarged phallus. The surgical management of children born with atypical genitalia is complex and is reviewed separately. Some groups have advocated avoiding all "cosmetic" genital surgery until the child is old enough to make an informed decision. (See "Management of the infant with atypical genitalia (disorder of sex development)", section on '46,XX CAH'.) CAH'.) Surgery should be done only in medical centers with substantial experience, and management ideally should be done by a multidisciplinary team that includes specialists in pediatric p ediatric endocrinology, pediatric surgery, surgery, urology, psychosocial services, and genetics [3 [3]. This topic is discussed in detail separately. (See "Management of the infant with atypical genitalia (disorder of sex development)", section on 'Overview of decisions about surgery'.) surgery'.) Prenatal diagnosis of CYP21A2  deficiency  deficiency and prenatal treatment of affected offspring are reviewed se parately. parately. (See 'Prenatal diagnosis' below diagnosis' below and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Prenatal therapy'.) therapy'.) Growth — Growth — Children with congenital adrenal hyperplasia (CAH) are at risk for early puberty and adult short stature. Exposure to high levels of sex hormones can induce early puberty and premature epiphyseal closure. Excess glucocorticoid exposure secondary to treatment may also suppress growth and contribute to adult short stature. Retrospective studies have shown that the final height of treated patients is independent of the degree of control of adrenal androgen concentrations, suggesting that both hyperandrogenism and hypercortisolism play a role in the observed short stature. A meta-analysis of data from 18 centers showed that the mean adult height of  patients with classic CAH was 1.4 standard deviations (10 cm) below the population mean [4 [4]. Patients with nonclassic CAH have a more favorable height prognosis but are also at risk for loss of adult height. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Growth'.) 'Growth'.) DIAGNOSIS — DIAGNOSIS — The diagnosis of classic 21-hydroxylase deficiency (21OHD) is based upon a very high serum concentration of 17-hydroxyprogesterone (17OHP), the normal substrate for 21-hydroxylase (figure (figure 1). 1). Most affected neonates have random concentrations greater than 3500 ng/dL (105 nmol/L). The diagnosis of classic 21OHD is almost always made in neonates (75 percent are salt-losing), and routine neonatal screening is now mandatory in many countries, including the United States [2,5 [2,5]. ]. The role of prena tal testing is described below. (See 'Prenatal diagnosis' below.) diagnosis' below.) Classic congenital adrenal hyperplasia (CAH) due to 21OHD results in one of o f two clinical syndromes: a saltlosing form or a non-salt-losing (simple-virilizing) form. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Infants/children'.) 'Infants/children'.) ●

Girls with either form present as neonates with atypical genitalia, with clitoral enlargement and a common urethral-vaginal orifice (urogenital sinus). Partial or complete fusion of the labial folds and rostral migration of  the urogenital orifice may also occur. Internal female reproductive organ s (uterus and ovaries) are normal. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Atypical genitalia'.) genitalia'.)

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In rare instances, the atypical genitalia may not be identified. Thus, prior to newborn screening, these affected females could present with a salt-losing adrenal crisis at one to two weeks of age. Historically, boys presented as neonates with a salt-losing adrenal crisis (hyponatremia, hyperkalemia, and failure to thrive) or as toddlers with signs of puberty (non-salt-losing form). Newborn males sho w no overt signs of CAH, although phallic enlargement and scrotal hyperpigmentation are sometimes present. With the advent of neonatal screening programs, affected males are typically diagnosed before they develop clinical symptoms [2 [2].

In countries where routine neonatal n eonatal screening is not available, a vailable, the diagnosis is sometimes made after infancy. (See 'Interpretation of results' below.) results' below.) Newborn screening — screening — In many countries, including the United States, neonatal screening for 21OHD is an approved part of the neonatal screening program. The screening test for 17OHP is measured using a filter paper  blood sample obtained by a heel puncture preferably between two and four days after birth. The assay used in most programs is a fluoroimmunoassay (DELFIA) [6 [ 6]. (See 'Interpretation of results' below.) results' below.) Interpretation of results — results — The characteristic biochemical abnormality for diagnosis at any age in patients with 21OHD is an elevated serum concentration of 17OHP, 17OHP, the normal substrate for 21-hydroxylase (figure (figure 1). 1). ●

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 A very high serum concentration of 17OHP in a randomly timed blood sample is diagnostic of classic 21hydroxylase deficiency. Most affected neonates have random concentrations greater than 3500 ng/dL (105 nmol/L) [7 [7]. All have concentrations greater than 1200 ng/dL (36 nmol/L). 17OHP may be elevated in 11beta-hydroxylase deficiency, but levels are 4 mm, lobulated surface, or abnormal echogenicity) had 92 percent sensitivity and 100 percent specificity in differentiating 25 neonates and children with untreated CAH from eight children with the disorder who had been treated and 19 children with other  conditions [28 [28]. ]. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)".) development)".) PRENATAL DIAGNOSIS — DIAGNOSIS — Prenatal diagnosis can be considered when a fetus is known to be at risk because of an affected sibling or when both partners are known to be heterozygous for one of the severe mutations, thus predicting a one-in-eight chance of female genital atypia. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Risk of classic CAH in offspring'.) offspring' .) Measurements of amniotic fluid 17-hydroxyprogesterone (17OHP), human leukocyte antigen (HLA) typing of fetal cells, and molecular analysis of fetal CYP21A2  genes  genes in amniocytes or chorionic villus samples have all been used as screening methods, although the molecular analysis of CYP21A2  genes is  genes is now the method of choice [29-31 29-31]. ]. This test is available commercially but is expensive and not necessarily ne cessarily covered by insurers. Noninvasive fetal DNA testing of the mother's plasma has correctly identified fetal congenital adrenal hyperplasia (CAH) status as early as five weeks gestation in 14 families [32 [32]. ]. Prenatal diagnosis also is undertaken if prenatal therapy is being used; that is discussed separately. If prenatal therapy is not planned, then prenatal diagnosis is not indicated, but it may be a parental choice. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Prenatal therapy'.) therapy'.)  Approximately 90 to 95 percent of CYP21A2  mutant  mutant alleles are detected using polymerase chain reaction (PCR) methodology that targets the 12 most common mutations. Although screening for the most common mutations may miss mutations in up to 10 percent of CAH patients [26 [26], ], if at least one mutation is detected, the patient can be evaluated further. CYP21A2  mutation  mutation analysis is not helpful in diagnosing other enzyme deficiencies as a possible cause of CAH. SOCIETY GUIDELINE LINKS — LINKS — Links to society and government-sponsored guidelines from selected countries and regions around t he world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".) deficiency".) SUMMARY — SUMMARY  — Over 95 percent of cases of congenital adrenal hyperplasia (CAH) are due to 21-hydroxylase deficiency (21OHD). It is one of the most common known autosomal recessive disorders. The clinical manifestations of classic 21OHD are described separately. separately. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".) deficiency".) ●

The characteristic biochemical abnormality in patients with classic 21 OHD is an elevated serum concentration of 17-hydroxyprogesterone (17OHP), the normal substrate for 21-hydroxylase, greater than 1200 ng/dL (36 nmol/L). Most affected neonates have concentrations greater than 3500 ng/dL (105 ng/dL (105 nmol/L). (See 'Newborn screening' above.) screening' above.)

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In many countries, neonatal screening for 21OHD is performed routinely in all newborns and begins with measurement of 17OHP in a dried, filter paper blood spot. (See 'Newborn screening' above.) screening' above.) False-positive results from neonatal screening are common with premature infants, and many screening programs have established reference ranges that are based upon weight and gestational age. Falsenegative results may occur as a result of maternal antenatal glucocorticoid use. (See 'Interpretation of  results' above results'  above and 'Effect of antenatal glucocorticoids' above.) glucocorticoids' above.) Treatment of classic 21OHD is reviewed elsewhere. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults" and adults" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".) children".)

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13. Sarafoglou K, Banks K, Kyllo J, et al. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA 2012; 307:2371. 14. Varness TS, Allen DB, Hoffman GL. Newborn screening for congenital adrenal hyperplasia h as reduced sensitivity in girls. J Pediatr 2005; 147:493. 15. Chan CL, McFann K, Taylor L, et al. Congenital adrenal hyperplasia and the second newborn screen. J Pediatr 2013; 163:109. 16. Gatelais F, Berthelot J, Beringue F, et al. Effect of single and multiple courses of prenatal corticosteroids on 17-hydroxyprogesterone levels: implication for neonatal screening of congenital adrenal hyperplasia. Pediatr Res 2004; 56:701. 17. Kösel S, Burggraf S, Fingerhut R, et al. Rapid second-tier molecular genetic analysis for congenital adrenal hyperplasia attributable to steroid 21-hydroxylase deficiency. Clin Chem 2005; 51:298. 18. Minutti CZ, Lacey JM, Magera MJ, et a l. Steroid profiling by tandem mass spectrometry improves the positive predictive value of newborn screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab 2004; 89:3687. 19. Soldin SJ, Soldin OP. OP. Steroid hormone analysis by tandem mass spectrometry. Clin Chem 2009; 55:1061. 20. Schwarz E, Liu A, Randall H, et al. Use of steroid profiling by UPLC-MS/MS as a second tier t est in newborn screening for congenital adrenal hyperplasia: the Utah experience. Pediatr Res 2009; 66:230. 21. Matern D, Tortorelli Tortorelli S, Oglesbee D, et al. Reduction of the false-positive rate in newborn screening by implementation of MS/MS-based second-tier tests: the Mayo Clinic experience (2004-2007). J Inherit Metab Dis 2007; 30:585. 22. Lacey JM, Minutti CZ, Magera MJ, et al. Improved specificity of newborn screening for congenital adrenal hyperplasia by second-tier steroid profiling using tandem mass spectrometry. Clin Chem 2004; 50:621. 23. Peter M, Janzen N, Sander S, et al. A case of 11beta-hydroxylase deficiency detected in a newborn screening program by second-tier LC-MS/MS. Horm Res 2008; 6 9:253. 24. El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet 2017; 390:2194. 25. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983; 57:320. 26. Finkielstain GP, 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. 27. Nordenström A, Thilén A, Hagenfeldt L, et al. Genotyping is a valuable diagnostic complement to neonatal screening for congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 1999; 84:1505. 28. Al-Alwan 28. Al-Alwan I, Navarro O, Daneman D, Daneman A. Clinical utility of adrenal ultrasonography in the diagnosis of congenital adrenal hyperplasia. J Pediatr 1999; 135:71. 29. Gueux B, Fiet J, Couillin P, et al. Prenatal diagnosis of 21-hydroxylase deficiency conge nital adrenal hyperplasia by simultaneous radioimmunoassay of 21-deoxycortisol and 17-hydroxyprogesterone in amniotic fluid. J Clin Endocrinol Metab 1988; 66:534. 30. Mornet E, Boue J, Raux-Demay M, et al. First trimester prenatal diagnosis of 21-hydroxylase deficiency by linkage analysis to HLA-DNA probes and by 17-hydroxyprogesterone determination. Hum Genet 1986; 73:358. 31. Lee HH, Chao HT HT,, Ng HT, HT, Choo KB. Direct molecular diagnosis of CYP21 mutations in congenital adrenal hyperplasia. J Med Genet 1996; 33:371.

32. New MI, Tong Tong YK, Yuen T, T, et al. Noninvasive prenatal diagnosis diagno sis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma. J Clin Endocrinol Metab 2014; 99:E1022. Topic 145 Version 16.0

GRAPHICS Clitoromegaly

Clitoromegaly in a 46,XX in fant with 21-hydroxylase deficiency. Courtesy of Christopher P Houk, MD and Lynne L Levitsky, MD Graphic 64870 Version 1.0

Synthetic defect in CYP21A2 (21-hydroxylase) deficiency

Pathways of adrenal steroid synthesis. A synthetic defect in 21-hydroxylase leads to diminished cortisol synthesis, increased release of corticotropin (ACTH), accumulation of 17hydroxyprogesterone (particularly after the administration of ACTH), possible virilization due to increased androgen production, and possible salt-wasting due to diminished production of  aldosterone and deoxycorticosterone. The numbers at the arrows refer to specific enzymes: 17α: 17α-hydroxylase (P450c17); 17,20: 17,20 lyase which is part of the P450c17 enzyme; 3β: 3β-hydroxysteroid dehydrogenase; 21: 21-hydroxylase (P450c21); 11β: 11β-hydroxylase; (P450c11); 18 refers to the two-step process of aldosterone synthase (P450c11as), resulting in the addition of an hydroxyl group that is then oxidized to an aldehyde group at the 18-carbon position; ?: unclear if pathway functions in vivo; DHEA: dehydroepiandrostenedione; 17KSR: 17-ketosteroid reductase; and A: aromatase. Graphic 81907 Version 4.0