Key Points
- All newborn screening programs should incorporate screening for congenital adrenal hyperplasia, and infants with positive screens should be referred to pediatric endocrinologists.
- Prenatal therapy for congenital adrenal hyperplasia should be avoided (except as part of ethically-approved protocols) due to incompletely defined postnatal risks.
- Healthcare professionals should inform all parents of pediatric patients with CAH (particularly girls with ambiguous genitalia) about surgical options, including delaying surgery until the child is older.
- All surgical decisions for minors should be the prerogative of families (i.e., parents with assent from older children) in joint decision making with experienced surgical consultants.
- Adolescents with congenital adrenal hyperplasia should start the transition to adult care several years prior to dismissal from pediatric endocrinology to ensure continuation of care throughout their entire life.
- Growing individuals with classic congenital adrenal hyperplasia should receive maintenance therapy with hydrocortisone and should avoid chronic use of more potent or long-acting glucocorticoids, which can have adverse side effects.
- Patients with congenital adrenal hyperplasia (and parents of minors) should seek mental health treatment to address any congenital adrenal hyperplasia-related psychosocial problems.
Diagnosis
Newborn Screening
- Endocrine Society (ES) recommends that all newborn screening programs incorporate screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. (1|⊕⊕⊕◯)
- ES recommends that first-tier screens use 17-hydroxyprogesterone assays standardized to a common technology with norms stratified by gestational age. (1|⊕⊕⊕◯)
Technical remark: Clinicians should be aware that immunoassays are still in use and remain a source of false-positive results. Specificity may be improved with organic extraction to remove cross-reacting substances.
- ES recommends that screening laboratories employ a second-tier screen by liquid chromatography–tandem mass spectrometry in preference to all other methods (e.g., genotyping) to improve the positive predictive value of congenital adrenal hyperplasia screening. (1|⊕⊕◯◯)
Technical remark: Laboratories utilizing liquid chromatography–tandem mass spectrometry should participate in an appropriate quality assurance program. Additionally, clinicians should realize that immunoassays lead to more false-positive results. Thus, if laboratory resources do not include liquid chromatography–tandem mass spectrometry, a cosyntropin stimulation test should be performed to confirm diagnosis prior to initiation of corticosteroid treatment.
Diagnosis of Congenital Adrenal Hyperplasia
- In infants with positive newborn screens for congenital adrenal hyperplasia, ES recommends referral to pediatric endocrinologists (if regionally available) and evaluation by cosyntropin stimulation testing as needed. (1|⊕⊕⊕◯)
- In symptomatic individuals past infancy, ES recommends screening with an early-morning (before 8 AM) baseline serum 17-hydroxyprogesterone measurement by liquid chromatography–tandem mass spectrometry. (1|⊕⊕⊕◯)
- In individuals with borderline 17-hydroxyprogesterone levels, ES recommends obtaining a complete adrenocortical profile after a cosyntropin stimulation test to differentiate 21-hydroxylase deficiency from other enzyme defects. (1|⊕⊕⊕◯)
- In individuals with congenital adrenal hyperplasia, ES suggests genotyping only when results of the adrenocortical profile after a cosyntropin stimulation test are equivocal, or cosyntropin stimulation cannot be accurately performed (i.e., patient receiving glucocorticoid), or for purposes of genetic counseling. (2|⊕⊕⊕◯)
Technical remark: Genotyping at least one parent aids in the interpretation of genetic test results because of the complexity of the CYP21A2 locus.
Figure 1. Fetal Adrenal Steroidogenesis
Table 1. Comparative Incidence of Classic CAH in Different Populations
| Country | Complete National Data? | Sample Size | 1/Incidence | PPV% (Term Infants or Overall) |
|---|---|---|---|---|
| Argentina (Buenos Aires) | No | 80436 | 8937 | 50 |
| Australia (Western Australia)a | No | 550153 | 14869 | N/A |
| Australia (New South Wales) | No | 185854 | 15488 | 1.8 |
| Australiaa | Yes | 18034 | N/A | |
| Brazil | No | 748350 | 14967 | |
| Brazil (state of Goias) | No | 82603 | 10325 | 28.6 |
| Brazil (state of Minas Gerais) | No | 159415 | 19927 | 2.1 |
| Brazil (state of Rio Grande do Sul) | No | 108409 | 13551 | 1.6 |
| China | No | 30000 | 6084 | |
| Croatia | Yes | 532942 | 14403 | |
| Cuba | Yes | 621303 | 15931 | 0.3 |
| Czech Republic | Yes | 545026 | 11848 | 1.6 |
| France | Yes | 6012798 | 15699 | 2.3 |
| Germany (Bavaria) | No | 1420102 | 12457 | 5 |
| India | No | 55627 | 6334 | |
| Japan (Sapporo) | No | 498147 | 20756 | 8 |
| Japan (Tokyo) | No | 2105108 | 21264 | 25.8 |
| New Zealand | Yes | 1175988 | 26727 | |
| Sweden | Yes | 2737932 | 14260 | 25.1 |
| United Kingdoma | Yes | 18248 | N/A | |
| United Arab Emirates | Yes | 750365 | 9030 | |
| Uruguay | Yes | 190053 | 15800 |
Data are from newborn screening except those designated as coming from national case registries.
Data are from studies published in 2008 and later. Earlier studies are summarized by van der Kamp and Wit 2004 (van der Kamp HJ, Wit JM. Neonatal screening for congenital adrenal hyperplasia. Eur J Endocrinol. 2004;151(Suppl 3): U71–U75) and Gidlof et al. 2014 (Gidlöf S, Wedell A, Guthenberg C, von Döbeln U, Nordenström A. Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population based study. JAMA Pediatr. 2014;168(6):567–574.).
a Data are from national case registries.
Figure 2. Diagnosis of 21OHD
