Adrenal Congenital Hyperplasia

Article Editor:
Virteeka Sinha
Updated:
11/7/2018 9:13:46 AM
PubMed Link:
Adrenal Congenital Hyperplasia

Introduction

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease emerging from mutations of genes for enzymes that lead to the biochemical steps of production of glucocorticoids, mineralocorticoids, or sex steroids from cholesterol by the adrenal glands. Most of these diseases involve the excessive or deficient production of sex steroids that can alter the development of primary or secondary sex characteristics in some affected infants, children, or adults.

Etiology

CAH most commonly results from mutations or deletions of CYP21A. This mutation produces a 21-hydroxylase deficiency in 90% of adrenal hyperplasia cases. Mutations or partial deletions that alter CYP21A also are common. The estimated prevalence is one case per 60 individuals in the general population and one in three in select populations. CAH which is caused by 21-hydroxylase deficiency is found in all populations whereas 11-beta-hydroxylase deficiency is more common in individuals of Iranian, Jewish, or Moroccan descent.

Epidemiology

In the United States, CAH is more common in Native Americans and Yupik Eskimos. Among Caucasians, the incidence is approximately 1 in 15,000.

Since all forms of CAH have an autosomal recessive pattern of inheritance, both sexes are equally affected. However, because of the accumulated testosterone or precursor hormones, the phenotypic expression may be different in both genders. CAH is usually obvious at birth or soon after because of the ambiguous genitals, early virilization, or salt wasting. Atypical cases may be recognized around puberty with the presence of virilizing signs or oligomenorrhea in females.

Pathophysiology

CAH is associated with a defective gene. The most common is the gene for 21-hydroxylase (95%), which is found on 6p21.3 as part of the human leukocyte antigen (HLA) complex. Inefficiency produced by the specific alleles found in each patient introduces variability. Milder degrees of inefficiency link to excessive sex hormone effects in childhood or adolescence. The mildest form interferes with ovulation and fertility in adults.

Histopathology

The histological features of CAH include the following:

  • Adrenal cortex hyperplasia.
  • Disorganized architecture of the adrenal medulla and cortex.
  • Lipoid deposits which represent cholesterol esters that have been unable to enter into the mitochondria for steroid synthesis.
  • Hypertrophy of the juxtaglomerular apparatus when salt wasting is present.

History and Physical

The symptoms of Congenital Adrenal Hyperplasia and include the following:

Mineralocorticoids Inadequacy

  • Vomiting as a result of salt-wasting leading to dehydration and death.

Excess Androgens 

  • Males: excessive facial hair, functional and average sized penis with extreme virilization (but no sperm).
  • Females: ambiguous genitalia, menstrual irregularity, infertility due to anovulation, enlarged clitoris, and shallow vagina.
  • Early pubic hair and rapid growth in childhood.
  • Precocious puberty or failure of puberty to occur.

Undervirilization may occur in XY males, which may result in apparently female external genitalia. In females, hypogonadism may cause sexual infantilism or abnormal pubertal development and infertility.

Evaluation

Female infants will have ambiguous genitalia because of exposure to high concentrations of androgens in utero. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common cause of ambiguous genitalia in genotypically normal female infants (46XX). Females less severely affected may present with early pubarche. Young women may present with oligomenorrhea polycystic ovaries and hirsutism (polycystic ovarian syndrome).

Males have no signs of CAH at birth. Some may present with hyperpigmentation and penile enlargement. Males with salt-wasting disease present early with hyponatremia and hypovolemia. Males with non-salt-wasting disease present later with signs of virilization. In rare forms, males are undermasculinized. Females have no signs or symptoms at birth.

Laboratory Studies

Genetic analysis may be helpful, but it is not necessary if classic clinical and laboratory findings are present.

In classic 21-hydroxylase deficiency, laboratory tests will show:

  • Hypoglycemia (due to hypocortisolism)
  • Hyponatremia (due to hypoaldosteronism)
  • Hyperkalemia (due to hypoaldosteronism)
  • Elevated 17alpha-hydroxyprogesterone

Classic 21-hydroxylase deficiency causes 17 alpha-hydroxyprogesterone blood levels greater than 242 nmol/L.

Neonatal screening programs typically have specific reference ranges by weight and gestational age because high levels may be seen in premature infants without congenital adrenal hyperplasia. Salt-wasting patients may have higher 17 alpha-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17 alpha-hydroxyprogesterone may not be elevated, but it will rise during a corticotropin stimulation test.

In many countries, children are screened for 21-hydroxylase at birth. This test will detect elevated levels of 17-hydroxyprogesterone. Detecting high levels can result in early treatment and a relatively normal life. 

Imaging Studies

Unless hemorrhage is suspected in the adrenal glands, imaging studies are not required in evaluating patients with CAH. However, in patients with ambiguous genitalia pelvic, ultrasound may be done to assess for other anomalies and define the anatomy of the urogenital tract.

Children with precocious puberty may benefit from a bone scan.

 Other Tests

  • A chromosomal study usually is done in infants with ambiguous genitalia to establish the gender.
  • Genetic testing is otherwise only necessary during pregnancy to counsel the patient.
  • Some centers routinely screen infants for 21 hydroxylase deficiency before a life-threatening salt-wasting crisis develops.

Treatment / Management

Treatment of CAH includes:

  • Supplying enough glucocorticoid to reduce hyperplasia and reduce overproduction of androgens and mineralocorticoids.
  • Providing replacement of mineralocorticoids and extra salt if deficient.
  • Providing testosterone or estrogen replacement at puberty if deficient.
  • Additional therapy, as needed, to optimize growth by delaying puberty or delaying bone maturation.

CAH is a recessive gene, so both the mother and father must be recessive carriers. Couples with the recessive CAH genes may prevent CAH through preimplantation genetic diagnosis.

Surgical Care

Infants with ambiguous genitalia need a surgical consult for corrective surgery. Surgery only is undertaken in a few selected infants and must be done by experienced surgeons. Surgery is not required for the majority of infants with mild forms of virilization.

In the past, some infants required bilateral adrenalectomies to manage severe virilization and prevent premature skeletal maturation- however, today this procedure is rarely done.

Long-Term Monitoring

Patients with CAH need lifelong follow up to monitor the doses of glucocorticoids and mineralocorticoids and monitor the side effects of these hormones

Prognosis

If the disorder is promptly diagnosed and treated, the prognosis for most patients is good. However, even though the physical deficits can be overcome, most patients have lifelong emotional issues that stem from the ambiguous genitalia. Other problems that can occur in these patients include:

  • Infertility.
  • Short stature.
  • Female gender identity issues.
  • Virilization issues in women.
  • Premature death when patients are not administered stress doses of corticosteroids/glucocorticoids during surgery, trauma or illness.

Pearls and Other Issues

Cortisol is an adrenal steroid hormone required for endocrine function that begins to be produced in the second month of fetal life. Poor cortisol production is a hallmark of CAH. Inefficient cortisol production results in elevated adrenocorticotropic hormone (ACTH). Increased ACTH stimulation induces hyperplasia of the steroid-producing cells of the adrenal cortex. The defect results in adrenal hyperplasia.

Cortisol deficiency in CAH is usually partial. The synthesis of cortisol shares steps with the creation of aldosterone, testosterone, and estradiol. The resulting excess or decrease production of these hormones produces multiple problems.

Prevention

Prenatal chorionic villus sampling or amniocentesis can detect CAH during pregnancy.