Congenital Adrenal Hyperplasia - CAH

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by several distinct enzymatic defects that result in changes in steroidogenesis. These disruptions cause irregular genital and sexual characteristics, and interfere with electrolyte balance. Newborn screening detects elevations in 17-hydroxyprogesterone (17-OHP). Other forms of CAH without significant 17-OHP increases are often not identified until later in life due to their more subtle clinical presentations. Initial testing generally involves 17-OHP testing and, if 17-OHP is increased, adrenocorticotropic hormone (ACTH) testing.

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Ambiguous genitalia or unexplainable electrolyte results in infancy
Premature sexual development in older children
Hirsutism and irregular menses in adult females

Laboratory Testing

Initial testing
- 17-OHP
  - If elevated, perform ACTH stimulation (cosyntropin)
    - Often unnecessary when there is marked elevation of 17-OHP
    - 17-OHP remains increased after stimulation in classic CAH
  - If nonclassic form is suspected in adult female, obtain 17-OHP at 0800 hours and during follicular phase of menstrual cycle
  - Further evaluation should include assessment of salt wasting
    - Serum sodium, potassium, and renin activity – expect hyponatremia, hyperkalemia, and increased renin in classic 21-hydroxylase deficiency CAH
Secondary testing
- Adrenal steroid quantitative panel – if ACTH stimulation is abnormal or if a marked elevation of 17-OHP is noted
  - 21-hydroxylase deficiency
    - Characterized by markedly elevated plasma 17-OHP
  - 11-beta-hydroxylase deficiency
    - Indicated by increased 11-deoxycorticosterone and 11-deoxycortisol levels
  - 17-hydroxylase (17-OH) deficiency
    - Characterized by increased pregnenolone, 11-deoxycorticosterone, and corticosterone, and decreased 17-hydroxypregnenolone (17-OH-pregnenolone)
  - 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency
    - Indicated by increased pregnenolone, 17-OH pregnenolone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS)
Testing in infants
- Karyotyping to rule out chromosomal disorder
- Pelvic ultrasonography to assess internal genital organs in females
- Assess glucose, electrolytes, liver function, and blood gases in infants suspected of acute adrenal insufficiency

Differential Diagnosis

Hirsutism, irregular menses
Salt wasting
- Adrenal insufficiency
Ambiguous genitalia
- Maternal hyperandrogenism
- Androgen-secreting tumor
- Chromosomal abnormality
Premature sexual development
- Adrenarche
- Androgen-secreting tumor
- Cushing syndrome

Screening

Newborn screening for CAH in most states – 17-OHP
- Threshold for positive tests is set relatively low to prevent missing true positives
- False positives common in premature infants, who tend to have increased 17-OHP
  - Markedly increased 17-OHP confirms disease
    - Follow up positive results with ACTH stimulation in all infants
- False negative may occur if maternal glucocorticoids are administered
Prenatal diagnosis
- Chorionic villus sampling or amniocentesis, 90-95% sensitive
- Allows for prenatal treatment of disease through administration of maternal glucocorticoid

Monitoring

For assessment of glucocorticoid replacement
- 17-OHP, androstenedione, and testosterone
  - Every 3 months during infancy and every 3-6 months thereafter
For assessment of mineralocorticoid replacement
- Blood pressure measurement
- Plasma renin/renin activity
- Aldosterone and potassium levels may also be helpful

Background

Epidemiology

Incidence
- 1/10,000-20,000 (Speiser, Endocrine Society, 2010)
Sex – M>F
Ethnicity
- Caucasians
  - 0.1-0.2% affected with nonclassical forms
- Ashkenazi Jews
  - 1-2% affected with nonclassical forms
- Higher prevalence of classic CAH in Alaskan Yupic Eskimos and residents of French island La Réunion

Risk Factors

Genetic
- Autosomal recessive inheritance
- Enzymatic defects include
  - 21-hydroxylase (CYP21A2 variant) – most common defect (>90%)
  - 11-beta-hydroxylase (CYP11B1 variant)
  - CYP17A1 deficiencies (CYP17A1 variant)
  - 17,20-lyase deficiencies
  - 3 beta-HSD (HSD3B2 variant)
  - Cytochrome P450 oxidoreductase deficiency
  - Hexose-6-phosphate dehydrogenase deficiency (H6PD variant)
  - PAPSS2 deficiency (PAPSS2 variant)
  - Congenital lipoid adrenal hyperplasia (StAR variants)
  - P450scc side chain cleavage enzyme deficiency (CYP11A1 variant)

Pathophysiology

Gene variants cause a block in adrenal glucocorticoid and mineralocorticoid synthesis pathways
21-hydroxylase deficiency
- Defective conversion of 17-OHP to 11-deoxycortisol
- Blocked steroid synthesis causes adrenal insufficiency and compensatory elevation of ACTH
- ACTH elevation causes adrenal hyperplasia and additional precursor synthesis
- Precursor excess is shunted into the androgen synthesis pathway, causing virilization in females and premature sexual development in males
11-beta-hydroxylase deficiency
- Impaired conversion of 11-deoxycortisol to cortisol
- Accumulation of 11-deoxycorticosterone (a potent mineralocorticoid) leads to mineralocorticoid excess with possible hypertension
17-alpha-hydroxylase/17,20-lyase deficiency
- Usually combined deficiency
- Decreased cortisol production and shunting of precursors into mineralocorticoid pathways
- Minimal testosterone or estrogen produced
3-beta-HSD deficiency
- Synthesis of all active steroid hormones is impaired

Clinical Presentation

21-hydroxylase deficiency
- Classic (more severe)
  - Presents during neonatal period
  - Ambiguous genitalia in females, virilization in males
  - Salt wasting in majority of patients (hyperkalemia, hyponatremia, dehydration)
- Nonclassic (late onset)
  - No neonatal genital ambiguity
  - Hirsutism
  - Irregular menses in females
  - Short stature
  - Acne
  - Infertility
  - Alopecia
11-beta-hydroxylase deficiency
- Hypertension, hypokalemia, and premature sexual development in males, ambiguous genitalia in females
17-alpha-hydroxylase deficiency
- Hypertension, hypokalemia, hypogonadism, lack of secondary sexual characteristics in females and males
- Isolated 17,20-lyase deficiency – males with under virilization, females with delayed pubarche
3 beta-HSD deficiency
- Feminized males, partial virilization of females
- Cortisol and aldosterone deficiency signs and symptoms
  - Feeding difficulty
  - Vomiting
  - Hyponatremia
  - Hyperkalemia
P450 oxidoreductase deficiency
- Severe virilization in females, severe under virilization in males
- No mineralocorticoid deficiency
- Craniofacial abnormalities
P450scc deficiency
- May be lethal due to potential insufficiency
- Defective synthesis of all adrenal hormones

ARUP Lab Tests

Primary Tests

Detect enzyme deficiencies causing CAH

17-Hydroxyprogesterone Quantitative by HPLC-MS/MS, Serum or Plasma 0092332

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Screen for 21-hydroxylase deficiency, the most common congenital adrenal insufficiency

Congenital Adrenal Hyperplasia Panel, 21-Hydroxylase Deficiency 2002283

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Components include androstenedione; 17-OHP; 17-hydroxypregnenolone, quantitative by LC-MS/MS; and dehydroepiandrosterone

Screen for 11-beta hydroxylase deficiency

Congenital Adrenal Hyperplasia Panel, 11-Beta Hydroxylase Deficiency 2002282

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Components include androstenedione; 17-OHP; testosterone; 11-deoxycortisol, quantitative by LC/MS-MS; and dehydroepiandrosterone

Detect accumulation of specific steroids as a result of enzyme deficiencies in CAH

Monitor patients with CAH

Adrenal Steroid Quantitative Panel by HPLC-MS/MS, Serum or Plasma 0092330

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Components include 11-deoxycortisol, quantitative; 17-OHP, quantitative by MS/MS; 17-hydroxypregnenolone, quantitative by MS/MS; and pregnenolone by MS/MS

Use to monitor treatment of individuals with classic or nonclassic CAH

Total testosterone values may not reflect optimal concentrations in all individuals

Congenital Adrenal Hyperplasia Treatment Panel 2002029

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Components include androstenedione; 17-OHP, quantitative by LC-MS/MS; and testosterone, females or children

Related Tests

Use to diagnose and manage diabetes mellitus and other carbohydrate metabolism disorders

Glucose, Plasma or Serum 0020024

Method: Quantitative Enzymatic

Electrolyte Panel 0020410

Method: Quantitative Ion-Selective Electrode/Enzymatic

The combined aldosterone/renin tests are preferred when screening for hyperaldosteronism

Refer to aldosterone/renin activity ratio or aldosterone and renin, direct with ratio

Renin Activity 0070105

Method: Quantitative Enzyme-Linked Immunosorbent Assay

Initial screening for hepatobiliary inflammation

Hepatic Function Panel 0020416

Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, direct; protein, total; and bilirubin, total

11-Deoxycortisol Quantitative by HPLC-MS/MS, Serum or Plasma 0092331

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

11-Deoxycorticosterone Quantitative by HPLC-MS/MS, Serum or Plasma 2008458

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Pregnenolone by LC-MS/MS, Serum or Plasma 0092334

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

17-Hydroxypregnenolone Quantitative by LC-MS/MS, Serum or Plasma 0092333

Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Medical Experts

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology and Automated Core Laboratory at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC, Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95(9): 4133-60. PubMed

General References

Antal Z, Zhou P. Congenital adrenal hyperplasia: diagnosis, evaluation, and management. Pediatr Rev. 2009; 30(7): e49-57. PubMed

Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009; 23(2): 181-92. PubMed

Lambert SM, Vilain EJ, Kolon TF. A practical approach to ambiguous genitalia in the newborn period. Urol Clin North Am. 2010; 37(2): 195-205. PubMed

Nimkarn S, New MI. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A paradigm for prenatal diagnosis and treatment. Ann N Y Acad Sci. 2010; 1192: 5-11. PubMed

Nimkarn S, New MI. Prenatal diagnosis and treatment of congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Nat Clin Pract Endocrinol Metab. 2007; 3(5): 405-13. PubMed

Trakakis E, Basios G, Trompoukis P, Labos G, Grammatikakis I, Kassanos D. An update to 21-hydroxylase deficient congenital adrenal hyperplasia. Gynecol Endocrinol. 2010; 26(1): 63-71. PubMed

Witchel SF. Congenital Adrenal Hyperplasia. J Pediatr Adolesc Gynecol. 2017; 30(5): 520-534. PubMed

Witchel SF. Nonclassic congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2012; 19(3): 151-8. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Kushnir MM, Neilson R, Roberts WL, Rockwood AL. Cortisol and cortisone analysis in serum and plasma by atmospheric pressure photoionization tandem mass spectrometry. Clin Biochem. 2004; 37(5): 357-62. PubMed

Kushnir MM, Rockwood AL, Roberts WL, Pattison EG, Owen WE, Bunker AM, Meikle W. Development and performance evaluation of a tandem mass spectrometry assay for 4 adrenal steroids. Clin Chem. 2006; 52(8): 1559-67. PubMed

Mao R, McDonald J, Cantwell M, Tang W, Ward K. The implication of de novo 21-hydroxylase mutation in clinical and prenatal molecular diagnoses. Genet Test. 2005; 9(2): 121-5. PubMed

Rogers MA, Liu J, Kushnir MM, Bryleva E, Rockwood AL, Meikle W, Shapiro D, Vaisman BL, Remaley AT, C Y Chang C, Chang T. Cellular pregnenolone esterification by acyl-CoA:cholesterol acyltransferase. J Biol Chem. 2012; 287(21): 17483-92. PubMed

Schwarz E, Liu A, Randall H, Haslip C, Keune F, Murray M, Longo N, Pasquali M. 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(2): 230-5. PubMed

Last Update: October 2019

Congenital Adrenal Hyperplasia - CAH

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Congenital Adrenal Hyperplasia - CAH. ARUP Consult^©. Retrieved October 17, 2019, from: https://arupconsult.com/content/congenital-adrenal-hyperplasia

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Congenital Adrenal Hyperplasia - CAH

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult