At a Glance

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of cortisol hormone biosynthesis. They are caused by 1 of several distinct enzyme defects that lead to defective adrenal gland steroid biosynthesis.

CAH results from three disturbances:

Lack of cortisol production

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Lack of aldosterone production

Over synthesis of androgens

These disturbances occur by 1 of 5 enzyme deficiencies that are crucial for adrenal steroid biosynthesis.

The most common form is due to the mutation/deletion of CYP21A2, which results in 21-hydroxylase enzyme deficiency (21-OHD). This enzyme converts 17-OH progesterone to 11-deoxycortisol and progesterone to deoxycorticosterone, respective precursors for cortisol and aldosterone. The other minor enzyme deficiencies include 11-beta hydroxylase deficiency (11BOHD) (CYP11B1), aldosterone synthase deficiency (ASD) (CYP11B2), 17-alpha hydroxylase deficiency (17AHD) (CYP17), and 3 beta hydroxy steroid dehydrogenase deficiency (3BOHD) (HSD3B2).

The clinical phenotype has been classified as:

Classic: Severe condition with prenatal onset, subclassified into salt losing or non salt losing (simply virilizing)

Nonclassic: Mild form of disease appearing later in life; some asymptomatic

The severe classic form occurs in 1 in 12,000 births worldwide. The carrier frequency of classic CAH is about 1 in 60. Salt-losing CAH accounts for 67% of the cases reported, and non-salt-losing CAH accounts for 33%. The prevalence of the nonclassic form is estimated as 1 in 1,000 in the white population. It is more frequent in certain ethnic populations, such as Ashkenazic Jews (1:27), Hispanics (1:53), Yugoslavs (1:63), and Italians (1:333). The mild, nonclassic form is a common cause of hyperandrogenism.

Clinical severity in patients depends on the degree of enzyme deficiency.

In female infants with classic form, genitalia are ambiguous with enlarged clitoris and a common urogenital sinus in place of a separate urethra or vagina. The other internal female organs are normal. Prader scale staging system (1-5) is used to classify severity in these patients to consider corrective surgery. In male infants, there are usually no signs at birth, except possible slight penile enlargement and hyper pigmentation.

The age at diagnosis depends on the severity of aldosterone deficiency. Usually, boys with salt-losing form present at 7-14 days of life with vomiting, weight loss, lethargy, dehydration, hyponatremia, and hyperkalemia. Boys with non-salt-losing form present with early viriliztion at 2-4 years of age.

In nonclassic CAH forms, patients present with hyperandrogenism in later childhood or early adulthood. They also present with infertility, hirsutism, oligomenorrhea or amenorrhea with polycystic ovaries, and acne.

Carriers usually have no symptoms or signs of excess androgens and do not need treatment.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Tests to confirm CAH include:

Early morning baseline serum 17OHP in symptomatic individuals

Complete individual adrenocortical profile after Adrenocorticotropic Hormone (ACTH) stimulation test to differentiate 21OHD from other enzyme defects and to make diagnosis in borderline cases (This is the best diagnostic test. This is the measurement of 17OHP before and after 60 minutes, intravenous bolus.)

Genotyping (This should be requested only when results of adrenocortical profile after ACTH stimulation tests are indeterminate or for purposes of genetic counseling.) (Table 1)

Table 1.
Enzyme Deficiency Prevalence in the diagnosed cases Steroids Elevated Steroids Decreased
21-OHD 90% 17-OHP Aldosterone/Cortisol
11-OHD 5-8% Androstenedione Deoxycortisol Cortisol, Aldosterone +/-
3BOHD Rare DHEA, 17-OHP Aldosterone, Cortisol, Testosterone
17-AHD Rare Corticosterone Cortisol, Testosterone
Chol Desmolase Rare None All

Screening for 21OHD should be performed in all new born screening programs, using a 2-tier protocol (initially by immunoassay with further evaluation by positive tests by HPLC-Mass Spectrometry).

First Tier screens for CAH should measure 17OHP on dried blood spots on the same dried blood spots or Guthrie cards as for other new born screening tests.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Because of significant diurnal variations in adrenal hormones, morning testing and blood collections are recommended.

Due to the lack of specificity in immunoassay for the measurements of various adrenal steroid metabolites, use of highly specific and HPLC-Mass Spectrometry methods for the detection of these hormones is recommended.

These steroids can be increased in premature infants and illness.

Neonatal hematocrits are wide (40-70%), which artifactually raises or lowers blood spot 17-OHP concentrations.

What Lab Results Are Absolutely Confirmatory?

Various enzymatic defects potentially causing CAH can be differentiated by measuring 17OHP, cortisol, deoxycorticosterone, 11-deoxycortisol, 17-OH pregnenolone, dehydroxyepiandrosterone (DHEA), and androstenedione after ACTH stimulation. Steroid profiling by HPLC-Mass Spectrometry in either serum or urine may supplant stimulation tests.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Result Interpretation for the diagnosis of CAH
  • Baseline 17OHP

  • >10,000 ng/dL (likely classic CAH)

  • 200-10,000 ng/dL (likely nonclassic CAH)

  • <200 ng/dL (likely unaffected or likely nonclassic CAH)

  • 17OHP Post ACTH stimulation test:

  • >10,000 ng/dL (classic CAH)

  • 1000-10,000 ng/dL (nonclassic CAH)

  • <990 ng/dL (likely unaffected or Heterozygote)

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

17OHP levels are normally higher at birth and decrease rapidly during the first few postnatal days. Diagnostic accuracy is poor the first 2 days.

Cut off values of 17OHP screening tests vary by lab and assay. Minimally elevated 17OHP levels might warrent second tier screen for the same blood sample, whereas moderately elevated 17OHP levels may be followed up with a repeated specimen. In this case, 17OHP levels by Mass Spectrometry method is recommended.