Congenital Adrenal Hyperplasia and Lab Testing

Congenital adrenal hyperplasia (CAH) is a collection of inherited problems of the adrenal gland. These tiny triangular organs are in the lower part of the body, just above the kidneys. They secret steroid hormones, namely cortisol, and aldosterone. In CAH, the shortage of enzymes required to produce these hormones leads to the abnormal functioning of the body. 

The adrenal gland converts cholesterol into pregnenolone. Then, specific enzymes complete the production of cortisol, aldosterone, and androgens. Dysfunctional enzymes or deficient ones result in abnormal production volumes of these substances. Insufficient levels of cortisol lead to an increased volume of the pituitary hormone, which is responsible for adrenal growth and hormone production (ACTH). The result is that the adrenal gland becomes oversized. Unfortunately, this increase in size and activity can’t compensate for the block in the production of cortisol. There are also Congenital Adrenal Hyperplasia forms that trigger excessive production of other steroid hormones known as androgens (such as 17-hydroxyprogesterone). Almost all cases of CAH, however, are due to a deficiency in the enzyme 21-hydroxylase (classical CAH), so we are going to focus solely on this in our article. 

One of the major effects of Congenital Adrenal Hyperplasia is a lowering of cortisol and aldosterone levels. In some cases, there’s also an increase in the androgens level. These male hormones can trigger modifications of genital organs in female infants. Often, these changes are visible at birth. Sometimes, the external genital organs on the newborn are ambiguous, making it hard to tell a male from a female. Although rare, CAH is the main cause of ambiguous external genitals in newborns. 

Male babies born with this condition will appear normal at birth, but they may experience early puberty caused by excess androgens. Female children may develop hirsutism (excess hair in otherwise hairless areas), as well as acne, clitoral enlargement, and other such signs of excess androgens. They will also suffer from irregular menstruation. Both males and females suffering from CAH have growth troubles. Children grow at a higher than normal rate, they experience early puberty, but they end up as shorter stature adults if left untreated. CAH may also trigger infertility by the time of adulthood. 

CAH enzyme deficiencies are the result of mutations in specific genes. These genes are autosomal recessive. This means the child needs to inherit the defective gene from both parents to develop the condition. Someone with only one copy will be a carrier but won’t experience any symptoms. If this individual meets someone who also has one copy of the mutated gene, and they have a baby together, the newborn will suffer from CAH. Scientists have identified different gene mutations. 

All but 10% of CAH cases are the result of a 21-hydroxylase deficiency, which is caused by a mutation in the CYP21A2 gene. These individuals may develop a classic (more severe) or nonclassic type of CAH. About three-quarters of all classic deficiency sufferers develop a “salt-wasting” CAH form with lower aldosterone levels, an excessive loss of fluids, low sodium, and high potassium levels. This is a life-threatening condition. 

Main Symptoms and Signs 

The symptoms of congenital adrenal hyperplasia depend on the type of enzyme deficiency and on the levels of cortisol, aldosterone, and androgens. These symptoms are variable in time, and they may worsen with stress or illness. 

The classic CAH type that leads to excess loss of fluids and salt can evolve to become a life-threatening adrenal crisis. 

The main signs and symptoms of adrenal crisis: 

  • Rapid heart rate, abnormal rhythm, low blood pressure 
  • Hyperkalemia (high potassium levels in the blood) 
  • Hypoglycemia (low blood sugar levels) 
  • Hyponatremia (low blood sodium levels) 
  • Irritability, confusion 
  • Dehydration 
  • Vomiting 
  • Females with classic CAH may also have ambiguous external genitals that aren’t clearly male or female. However, their reproductive system is normal (they have a normal uterus, ovaries, and fallopian tubes). 

Symptoms and signs of excess androgens in boys and girls in childhood and puberty: 

  • Accelerated growth (tall children end up as short adults) 
  • Deep voice 
  • Acne 
  • Enlarged penis in male sufferers (and enlarged clitoris in female sufferers) 
  • Hirsutism in females (excess hair on face and body) 
  • Infertility (or severe fertility issues) 
  • Irregular menstrual cycles in female sufferers 
  • Excess muscle growth 
  • Early growth of pubic and armpit hair 
  • Laboratory Tests 

Here are the main objectives of the congenital adrenal hyperplasia testing: 

  • Screening of all newborns for 21-hydroxylase deficiency 
  • Confirmation of the condition in those with positive screens 
  • Confirmation of the diagnosis in those with symptoms 
  • Determine the carrier status of an individual who has a family member with 21-hydroxylase deficiency 
  • Determine the chromosomal sex (XX or XY) of a newborn in case of ambiguous genitals 
  • Monitor and adjust CAH treatment 
  • Monitor the health evolution of an individual with adrenal crisis 
  • Detect 21-hydroxylase deficiency during pregnancy (not very frequent) 
  • Identify or exclude other types of CAH other than 21-hydroxylase deficiency 

The treatment stages may include the following: 

Screening 

  • Newborn screening for 21-hydroxylase deficiency is part of the routine testing in the United States. Unfortunately, it doesn’t help to identify infants with other types of CAH. Also, this screening may generate false positives. 
  • Prenatal testing with amniocentesis or chorionic villus analysis. 

Diagnose and Detection 

17-OHP – this test may show highly elevated numbers with 21-hydroxylase deficiency 

ACTH stimulation – the test measures the blood cortisol levels before and after a synthetic ACTH injection. If the adrenal glands are normal, cortisol levels will increase as a result of the ACTH injection; this isn’t a widely used test, though. 

In case 17-OHP is elevated, doctors may order additional tests that may include any of the following: 

  • Androstenedione 
  • Testosterone 
  • 11-deoxycortisol 
  • Dehydroepiandrosterone sulfate (DHEAS) 
  • 17-hydroxypregnenolone 
  • Pregnenolone 
  • Aldosterone and renin – to check whether these substances are within normal limits 
  • Chromosome analysis (karyotyping) – to find out a baby’s gender by identifying their chromosomes (XX (female) or XY (male)) 
  • Genetic testing – useful for detecting gene mutations; not usually required for a firm diagnosis but may be used for prenatal detection. It can also be useful for detecting gene mutations in family members to help determine carrier status. This test can detect the most common mutations. If a family is already known to have a specific mutation, testing should include that mutation. 
  • Treatment Monitoring (Tests Repeated Every Few Months) 
  • 17-OHP 
  • Androstenedione 
  • Testosterone 
  • Renin 
  • Overall Health Monitoring 
  • Comprehensive Metabolic Panel