Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH)


Introduction

  • Also k/as Adrenogenital syndrome.
  • Autosomal recessive disorders that disrupt adrenal steroidogenesis.
  • In this disorder, there is a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both. 
  • The most common form is due to 21-hydroxylase deficiency associated with mutations in the CYP21A2 gene which is located at chromosome 6p21, accounting for more than 90% of cases.
  •  In a female most common cause of ambiguous genitalia is congenital adrenal hyperplasia.
  • Development of the internal genitalia (i.e. Mullerian duct and its derivatives) is normal in females with classical CAH. 

Etiology & Molecular Genetics

  • Congenital adrenal hyperplasia (CAH) is a group of genetic conditions that can be caused by a change (mutation) in several different genes: 
  • 21-hydroxylase deficiency is caused by mutations in the CYP21A2 gene
  • 3-beta-hydroxysteroid dehydrogenase deficiency is caused by mutations in the HSD3B2 gene
  • 11-beta-hydroxylase deficiency is caused by mutations in the CYP11B1 gene
  • Cytochrome P450 oxidoreductase deficiency is caused by mutations in the POR gene.
  • 17-hydroxylase deficiency is caused by mutations in the CYP17A1 gene
  • Congenital lipoid adrenal hyperplasia is caused by mutations in the STAR gene

Pathophysiology

· ACTH acts on Adrenal gland & from the adrenals following hormones are produced

  1. Corticosteroid
  2. Mineralosteroid
  3. Progesterone
  4. Androgens
  • When there is 21 hydroxylase deficiency it leads to reduced cortisol & mineralocorticoid levels.
  • Reduced cortisol acts on ACTH and increases the production by inhibiting negative feedback mechanism.
  • Reduced mineralocorticoid will lead to salt and water wasting.
  • When there is increased ACTH it will further increase progesterone & 17-OH progesterone (used as a screening test).
  • Also, this leads to increase androgens in intrauterine life, which is responsible for virilization, ambiguous genitalia in females & heterosexual precocious puberty.

Types 

There are two major types of congenital adrenal hyperplasia:

  1. Classic CAH. This form is rarer and is usually detected in infancy. Approximately two-thirds of people who have classic CAH have what’s known as the salt-losing form, while one-third have what’s referred to as the simple-virilizing form.
  2. Nonclassic CAH. This form is milder and more common, and may not become evident until childhood or early adulthood.

Physical Characteristics in Females

Signs and symptoms of CAH vary, depending on which gene is defective and the level of enzyme deficiency.

  • Genotype = 46XXO.
  • Gonads = ovaries.
  • Uterus and vagina are present, as Mullerian duct develops normally, but remain infantile therefore failure to menstruate
  • Vulva and introitus are affected. There is clitoromegaly and the genital folds fuse to form penile urethra rather than labia minora. & Labia majora are fused which appears like a scrotum.
  • Heterosexual precocious puberty: Pubic hair and axillary hair appear and the voice deepens by the age of 2-4years. (since these characteristics are dependent on androgen).
  • Associated metabolic abnormalities (d/ t decreased aldosterone): Hyponatremia, hyperkalemia, and hypotension.
  • Have high chances of short stature as adults.
  • Nonclassical or late-onset CAH there is no genital ambiguity at birth and the usual presentation is androgen excess at puberty and hence it is a differential diagnosis of PCOD.

Investigation

  • USG shows the presence of uterus, vagina, fallopian tubes and ovaries. (Thus, all patients are potentially fertile)
  • Sex chromatin study: shows positive Barr body.

(Note: Whenever a child presents with ambiguous genitalia always do karyotyping)

Screening test

  • Measure serum 17-OH-progesterone
  • 200-800 mg; do diagnostic test i.e. ACTH stimulation test. If after ACTH levels >1500 mg its diagnostic of CAH.
  • >800mg; definitive diagnosis of CAH.

 Treatment 

  • Mineralocorticoids – give to all age groups.
  • Corticosteroids- differ in different groups.
  • Surgery- Surgery for ambiguous genitalia i.e. corrective surgery is the removal of phallus at 5 years Later on McIndoe vaginoplasty is done.
  • The best approach is an early prenatal diagnosis by chorionic villi sampling with rapid sex determination (FISH for the X and Y chromosome) and Genotyping. Treatment should be given to only those mothers with an affected female child.

 Choice of corticosteroid in treating CAH

Age

Corticosteroid of Choice

In neonate, childhood and until puberty (before the closure of epiphysis) Short-acting corticosteroid i.e. Hydrocortisone (long-acting can adversely affect the growth)
After the closure of epiphysis Long-acting corticosteroid either Dexamethasone/prednisolone
At reproductive age In these females fertility is decreased but they can conceive

  1. Non-pregnant female with CAH
  2. Pregnant female with CAH who is carrying male fetuses Or an unaffected female fetus.
  3. Pregnant female with CAH with an affected female fetus
 

  •  for 1. & 2. DOC = Hydrocortisone as it does not cross the placenta

 

  • for 3. DOC = Dexamethasone as it crosses the Placenta

 

  • Dexamethasone should be given to prevent fetal female genital virilization as dexamethasone is not metabolized by the placenta and crosses effectively into the fetal circulation.
  • For maximum benefit-treatment should begin at 4 to 5 weeks of gestation and not later than 8 weeks.

 Complications

  • Adrenal crisis because they have very low levels of cortisol in the blood. This can cause diarrhea, vomiting, dehydration, low blood sugar levels and shock. 
  • Adrenal crisis is a life-threatening medical emergency that requires immediate treatment.
  • Aldosterone may also below, which leads to dehydration and low sodium and high potassium levels. 
  • The nonclassic form of CAH doesn’t cause an adrenal crisis.
  • Males and females who have either classic or nonclassic CAH may also experience fertility problems.

Exam Important

  • Congenital adrenal hyperplasia is the M/c cause of ambiguous genitalia in females.
  • M/c enzyme deficiency in CAH is 21 hydroxylase deficiency.
  • Least common Enzyme deficiency 3β- HSD i.e. Hydroxysteroid dehydrogenase.
  • Nonclassical or late-onset CAH there is no genital ambiguity at birth and the usual presentation is androgen excess at puberty and hence it is a differential diagnosis of PCOD.
  • Development of the internal genitalia (i.e. Mullerian duct and its derivatives) is normal in females with classical CAH because the excess androgen is derived from adrenals and the ovaries are normal so they produce neither anti-Mullerian hormone nor significant amount of androgen to promote Wolffian duct development.
  • Surgery for ambiguous genitalia i.e. corrective surgery is the removal of phallus at 5 years. Later on, MC indoe vaginoplasty is done.
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