Cogenital-Adrenal-Hyperplasia

INTRODUCTIONDefective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol accounts for more than 95 percent of cases of congenital adrenal hyperplasia (CAH) [1,2]. This conversion is mediated by 21-hydroxylase due to mutations in the CYP21A2 gene. Based upon neonatal screening studies that detect classic CAH, 21-hydroxylase deficiency (21OHD) is one of the more common inherited disorders. 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 separately. (See “Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency” and “Treatment 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” and “Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency”.) CLINICAL MANIFESTATIONSThe clinical spectrum of disease ranges from the most severe to mild forms, depending on the degree of 21-hydroxylase deficiency (21OHD). Three main clinical phenotypes have been described: classic salt-losing, classic non-salt-losing (simple virilizing), and nonclassic (late-onset): ●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)”.) ●Males with the salt-losing form who are not identified by neonatal screening present with failure to thrive, dehydration, hyponatremia, 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 odor). ●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”.) Infants/children Atypical genitalia — 46,XX infants with classic 21OHD are born with atypical genitalia characterized by clitoral enlargement (picture 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)”.) Affected 46,XY infants are normal appearing at birth but may have subtle findings such as hyperpigmentation 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 congenital adrenal hyperplasia’.) 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 endocrinology, pediatric surgery, urology, psychosocial services, and genetics [2,3]. 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’.) Prenatal diagnosis of CYP21A2 deficiency and prenatal treatment of affected offspring are reviewed separately. (See ‘Prenatal diagnosis’ below and “Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children”, section on ‘Prenatal therapy’.) 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]. 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’.) DIAGNOSISThe 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 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]. The role of prenatal testing is described below. (See ‘Prenatal diagnosis’ below.) Classic congenital adrenal hyperplasia (CAH) due to 21OHD results in one of two clinical syndromes: a salt-losing 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’.) ●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 organs (uterus and ovaries) are normal. (See “Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency”, section on ‘Atypical genitalia’.) ●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 show 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]. In countries where routine neonatal screening is not available, the diagnosis is sometimes made after infancy. (See ‘Interpretation of results’ below.) Newborn 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]. (See ‘Interpretation of results’ below.) Interpretation of results — The characteristic biochemical abnormality for diagnosis at any age in patients with 21OHD is an elevated serum concentration of 17OHP, the normal substrate for 21-hydroxylase (figure 1). ●A very high serum concentration of 17OHP in a randomly timed blood sample is diagnostic of classic 21-hydroxylase deficiency. Most affected neonates have random concentrations greater than 3500 ng/dL (105 nmol/L) [7]. All have concentrations greater than 1200 ng/dL (36 nmol/L). 17OHP may be elevated in 11-beta-hydroxylase deficiency, but levels are <1200 ng/dL (36 nmol/L). ●The biochemical findings are less severe in patients with the nonclassic form of the disorder. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".) ●Additional lab testing that should be performed once a diagnosis is made is described below. (See 'Additional lab testing' below.) ●False-positive results from neonatal screening are common with premature and sick infants [8,9], and many screening programs have established reference ranges that are based upon birth weight and gestational age [10,11]. Although most laboratories in the United States use birth weight-adjusted cutoffs [2], gestational age criteria have been shown to improve the positive predictive value of screening [12]. ●Some studies now suggest that there is a substantial risk of false-negative results for the neonatal screening for CAH, particularly in girls [13,14]. This was best illustrated in a population-based study of all newborns screened in Minnesota from 1999 to 2010. Of the 838,241 newborns screened, 52 were diagnosed with classic CAH, but 15 cases (nine girls, six boys) were missed, for a false-negative rate of 22.4 percent (95% CI 14-34). Among the nine females missed by screening, five had further evaluation and were diagnosed because they had atypical genitalia, but three others had atypical genitalia and were not diagnosed until three months to six years. Thus, newborns with findings suggestive of CAH (eg, atypical genitalia) should undergo further endocrine evaluation even if the neonatal screening test is negative. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)".) ●To minimize the problem of false-negative results, some states in the United States perform a second routine screening for CAH in all newborns between 8 to 14 days of life. While sensitivity and positive predictive value might be improved by this approach, the data are not definitive, there are increased costs, and universal adoption of second screening has not been recommended [15]. Effect of antenatal glucocorticoids — Administration of antenatal glucocorticoids (eg, betamethasone), particularly multiple courses (administered to induce pulmonary maturation in pregnancies with expected preterm delivery), may decrease 17OHP levels in filter paper blood, increasing the risk of false-negative results [16]. Repeat screening for CAH at one to two weeks of age should therefore be performed in infants whose mothers have received multiple courses of antenatal glucocorticoids; salt loss should be carefully monitored in the interim between screening samples. Mass spectrometry — The positive predictive value of the filter paper screening is increased by using tandem mass spectrometry as a second-tier test [17-20]. Some states use a ratio of the sum of 17OHP and androstenedione divided by cortisol from a separate filter paper as the second-tier test with reduction of false-positive rates [20,21]. The use of tandem mass spectrometry rather than antibody-based assays also improves throughput and reduces the time to obtain a result [22]. However, the test is expensive and is not widely available as part of neonatal screening programs. ADDITIONAL LAB TESTING ●If a baby tests positive for congenital adrenal hyperplasia (CAH) during neonatal screening, follow-up 17-hydroxyprogesterone (17OHP), preferably measured by tandem mass spectrometry, and electrolytes should be performed. If the 17OHP level remains high, immediate referral to a pediatric endocrinologist is warranted. ●Although a cosyntropin (ACTH) stimulation test is the gold standard for the diagnosis of CAH, it is not always necessary to make the diagnosis of classic CAH; infants with classic CAH have levels of basal adrenocortical hormone precursors that are markedly elevated due to a highly stimulated adrenal cortex. To assess borderline cases, the standard high-dose (250 mcg cosyntropin) test, not the low-dose (1 mcg) test, should be used. This is preferred over genetic testing and can be done in an outpatient setting by a pediatric endocrinologist. If the diagnosis of CAH is highly probable (ie, random 17OHP >10,000 ng/dL, and electrolyte abnormalities or atypical genitalia in female infant), treatment should be instituted immediately and a cosyntropin test is not necessary. ●To define the metabolic defect in infants, serum concentrations of 11-deoxycortisol, 17-hydroxypregnenolone, cortisol, androstenedione, and dehydroepiandrosterone (DHEA) should also be measured, listed in order of priority. 17OHP might be elevated in rare types of CAH, such as P450 oxidoreductase deficiency, 11-hydroxylase deficiency and 3-beta-hydroxysteroid dehydrogenase deficiency; these should be considered [9,23,24]. ●A distinction between the salt-wasting and non-salt-losing (simple-virilizing) forms of 21-hydroxylase deficiency (21OHD) is not necessary; clinical management is the same, and there is a continuum of disease severity. However, patients with the most complete enzyme deficiency typically have the highest 17OHP levels [25]. Nonclassic CAH is generally not detected with newborn screening or random steroid levels. ●The majority of patients with classic 21OHD have clinically relevant mineralocorticoid deficiency and are at risk for volume depletion, hyponatremia, and hyperkalemia. Patients are also at risk for hypoglycemia during an adrenal crisis [1]. Elevated plasma renin activity indicates aldosterone deficiency but is difficult to assess in the newborn period. ●Other abnormalities that may be present in either form (but mostly in the classic form) include high serum concentrations of androstenedione, 3-alpha-androstanediol glucuronide, testosterone, 21-deoxycortisol, and progesterone, and increased urinary excretion of metabolites of cortisol precursors, particularly pregnanetriol, pregnanetriol glucuronide, and 17-ketosteroids. (Pregnanetriol and its glucuronide are the major metabolites of 17OHP, and 17-ketosteroids are metabolites of androgens such as testosterone.) (See “Adrenal steroid biosynthesis”.) Role of genetic testing — Genetic testing, which detects approximately 90 to 95 percent of mutant alleles [26], can also be used to evaluate borderline cases [27]. Genetic testing should only be done if the biochemical testing is equivocal or for purposes of genetic counseling and can be costly. ADRENAL ULTRASOUNDAdrenal ultrasonography is another potential adjunctive test for congenital adrenal hyperplasia (CAH) in neonates with atypical genitalia and/or life-threatening salt loss, when the diagnosis is equivocal based upon other testing. In a retrospective analysis of 52 children with atypical genitalia or salt-wasting crises, abnormal adrenal ultrasonography (ie, adrenal limb width >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]. (See “Evaluation of the infant with atypical genitalia (disorder of sex development)”.) PRENATAL DIAGNOSISPrenatal 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’.) Measurements of amniotic fluid 17-hydroxyprogesterone (17OHP), human leukocyte antigen (HLA) typing of fetal cells, and molecular analysis of fetal CYP21A2 genes in amniocytes or chorionic villus samples have all been used as screening methods, although the molecular analysis of CYP21A2 genes is now the method of choice [29-31]. This test is available commercially but is expensive and not necessarily 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]. 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’.) Approximately 90 to 95 percent of CYP21A2 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], if at least one mutation is detected, the patient can be evaluated further. CYP21A2 mutation analysis is not helpful in diagnosing other enzyme deficiencies as a possible cause of CAH. SOCIETY GUIDELINE LINKSLinks to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See “Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency”.) SUMMARYOver 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. (See “Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency”.) ●The characteristic biochemical abnormality in patients with classic 21OHD 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 nmol/L). (See ‘Newborn screening’ above.) ●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.) ●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. False-negative results may occur as a result of maternal antenatal glucocorticoid use. (See ‘Interpretation of results’ above and ‘Effect of antenatal glucocorticoids’ above.) ●Treatment of classic 21OHD is reviewed elsewhere. (See “Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults” and “Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children”.) DISCLOSUREThe views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005; 365:2125. 2. 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; 103:4043. 3. 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. 4. Eugster EA, Dimeglio LA, Wright JC, et al. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr 2001; 138:26. 5. Kaye CI, Committee on Genetics, Accurso F, et al. Newborn screening fact sheets. Pediatrics 2006; 118:e934. 6. Gonzalez RR, Mäentausta O, Solyom J, Vihko R. Direct solid-phase time-resolved fluoroimmunoassay of 17 alpha-hydroxyprogesterone in serum and dried blood spots on filter paper. Clin Chem 1990; 36:1667. 7. 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. 8. Cavarzere P, Samara-Boustani D, Flechtner I, et al. Transient hyper-17-hydroxyprogesteronemia: a clinical subgroup of patients diagnosed at neonatal screening for congenital adrenal hyperplasia. Eur J Endocrinol 2009; 161:285. 9. Coulm B, Coste J, Tardy V, et al. Efficiency of neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children born in mainland France between 1996 and 2003. Arch Pediatr Adolesc Med 2012; 166:113. 10. Olgemöller B, Roscher AA, Liebl B, Fingerhut R. Screening for congenital adrenal hyperplasia: adjustment of 17-hydroxyprogesterone cut-off values to both age and birth weight markedly improves the predictive value. J Clin Endocrinol Metab 2003; 88:5790. 11. van der Kamp HJ, Oudshoorn CG, Elvers BH, et al. Cutoff levels of 17-alpha-hydroxyprogesterone in neonatal screening for congenital adrenal hyperplasia should be based on gestational age rather than on birth weight. J Clin Endocrinol Metab 2005; 90:3904. 12. Steigert M, Schoenle EJ, Biason-Lauber A, Torresani T. High reliability of neonatal screening for congenital adrenal hyperplasia in Switzerland. J Clin Endocrinol Metab 2002; 87:4106. 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 has 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 al. 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. 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 test in newborn screening for congenital adrenal hyperplasia: the Utah experience. Pediatr Res 2009; 66:230. 21. Matern D, 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; 69:253. 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, 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 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 congenital 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, Ng HT, Choo KB. Direct molecular diagnosis of CYP21 mutations in congenital adrenal hyperplasia. J Med Genet 1996; 33:371. 32. New MI, Tong YK, Yuen T, et al. Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma. J Clin Endocrinol Metab 2014; 99:E1022.