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Congenital Adrenal Hyperplasia

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Congenital Adrenal Hyperplasia

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Congenital Adrenal Hyperplasias

Overview

Congenital adrenal hyperplasia, in its most common form, affects 1 in 15 thousand live births.

Congenital adrenal hyperplasia (CAH), includes a group of autosomal recessive disorders of adrenal cortex steroidogenesis due to enzyme deficiencies.

Enzyme deficiencies along these biosynthetic pathways lead to the accumulation of hormones proximal to the enzyme – so, for example, ACTH, a key pre-cursor hormone, often "builds up" and is shunted towards excessive androgen.

"Classic" vs. "nonclassic" forms
Classic forms refer to disorders in which the enzyme deficiency and clinical presentation is most severe, whereas, in the nonclassic forms, up to 50% of enzyme activity is retained, and disease manifestation is less severe.

Classic congenital adrenal hypertension, which is most often caused by deficiencies of 21 alpha-hydroxylase, can lead to acute adrenal failure and death in infancy.

  • Thus, in the US, we screen for elevated levels of 17-hydroxyprogesterone (17-OHP), in newborns.

Recall that, in the biosynthetic pathway for cortisol production, the hormone 17-OHP is converted to 11-deoxycortisol by 21 alpha-hydroxylase; thus, deficiency of this enzyme causes elevated levels of 17-OHP.

Before we learn about enzyme deficiencies leading to CAH, let's do a quick review of adrenal cortex physiology.

First, indicate the three layers of the adrenal cortex, from outer to inner:

  • Zona glomerulosa, which is where the mineralocorticoids, such as aldosterone, are produced.
  • Zona fasciculata, which is where the glucocorticoids, such as cortisol, are produced; note that some androgens are also produced in this layer.
  • Zona reticularis, which is where the androgens dehydroepiandrosterone (DHEA) and Androstenedione (A4) are produced.

Recall that it's the presence of key enzymes in each of these layers that determines their hormone products; thus, deficiencies of those enzymes impair hormone production.

Types of CAH:

We'll create a table to organize the causes of congenital adrenal hyperplasia (CAH).

  • For each enzyme, we'll list the organs affected and the hormonal and potassium profile; whether it's a salt-wasting disorder, and the clinical presentation.

21 alpha-hydroxylase
Deficiencies are due to mutations in the gene CYP21A2.
Deficiencies in this enzyme account for 90-95% of all cases of CAH.

The adrenal glands are affected

Increased levels of:

  • 17OHP (from interrupting the cortisol pathway), 21-deoxycortisol (another hormone precursor), androstenedione (from shunting of common cortex precursor hormones), renin, and potassium, and,

Decreased levels of: cortisol and aldosterone.

There are two forms of this CAH:

Classic
The classic form presents with salt-wasting approximately 2-3 weeks after birth.
The classic form can cause adrenal crisis, with dehydration, hypoglycemia, hyperkalemia, and hyponatremia. It may be fatal.

  • 46, XX newborns have ambiguous genitalia, due to excessive fetal androgen exposure, but 46, XY genitalia are typical. Be aware that the virilized genital anomalies of 46, XX newborns can include clitoromegaly, perineal hypospadias, and fusion of the urethral and labioscrotal folds can give rise to a phallus with a meatus and a fused but empty scrotum – thus, these newborns may be mistaken for males with undescended testes.
  • Excessive androgen exposure post-birth can cause early pubarche (the physical manifestation of adrenarche, including the appearance of pubic and axillary hair, and acne) and unusually rapid skeletal growth.

Non-classic
NCAH is due to 21 alpha-hydroxylase deficiency, newborns have enough aldosterone production to avoid salt-wasting and adrenal crisis.
With up to 50% of enzyme activity, we see fewer problems due to glucocorticoid or mineralocorticoid deficiencies. However, due to excess androgens, we can expect early pubarche.

  • 46, XX patients present with hirsutism and menstrual irregularities that impair fertility; manifestations can often look like PCOS.
  • 46, XY patients often go undiagnosed until familial studies are performed.

11 beta-hydroxylase
The second most common cause of congenital adrenal hyperplasia is deficiency of the enzyme 11 beta-hydroxylase due to mutations in the gene CYP11B1.
This enzyme deficiency affects the adrenal glands.

Increased levels of:
11-deoxycortisol (from the cortisol pathway), deoxycorticosterone (DOC) (from the aldosterone pathway), androstenedione, and mild elevation of 17OHP.

Decreased levels of:
Cortisol, aldosterone, renin, and potassium.

This is not a salt-wasting disorder, and usually presents in the classic form.

  • Excessive levels of ACTH suppress the renin-angiotensin-aldosterone system, which leads to ECF volume expansion and hypertension.
  • 46, XX patients are virilized.
    The non-classic form of this disorder is rare, and present similar to NCAH due to 21 alpha-hydroxylase deficiency with possible hypertension.

Next, we'll learn about two forms of CAH where androgens are not universally elevated.

17 alpha-hydroxylase
Deficiencies of 17 alpha-hydroxylase are due to mutations in the CYP17 gene.
Both the adrenal glands and gonads are affected.

Increases in:
DOC, corticosterone (both from the aldosterone pathway), and progesterone.

Decreases in:
Cortisol, aldosterone, 17OHP, DHEA, androstenedione, renin, and potassium.

This is not a salt-wasting disorder, and patients often present with hypertension; elevated corticosterone levels prevent adrenal crisis (corticosterone has mineralocorticoid actions).

Due to androgen deficiencies, 46, XY newborns present with ambiguous genitalia and undescended testes.
46, XX children will have puberty failure (no secondary sex development).

3 beta-hydroxysteroid dehydrogenase type 2
Deficiencies of 3 beta-hydroxysteroid dehydrogenase type 2 are due to mutations in HSD3B2.
Both the adrenal glands and the gonads are affected.

Increases in:
DHEA (from the androgen pathway) and renin.

Decreases in:
Cortisol, aldosterone, DOC, 11-deoxycortisol, 17OHP, progesterone, and androstenedione.

This IS a salt-wasting disorder, so watch for adrenal crisis in infants.

Due to the deficiency of testosterone, 46, XY newborns are under-virilized, with possible perineal hypospadias.
Due to the increase in DHEA, 46, XX newborns are virilized; children may experience early pubarche with hirsutism, acne, and menstrual irregularities.

As you review these enzyme deficiencies, it is highly recommended that you trace their actions in our tutorial on adrenal cortex hormone biosynthesis to better understand why some hormones are increased and decreased.

References

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  • NORD (National Organization for Rare Disorders). "Congenital Adrenal Hyperplasia." Accessed July 7, 2021. https://rarediseases.org/rare-diseases/congenital-adrenal-hyperplasia/.
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  • Eshragh, Nazaneen, Luong Van Doan, Kara J. Connelly, Sara Denniston, Sharon Willis, and Stephen H. LaFranchi. "Outcome of Newborn Screening for Congenital Adrenal Hyperplasia at Two Time Points." Hormone Research in Paediatrics 93, no. 2 (2020): 128–36. https://doi.org/10.1159/000508075.
  • Hannah-Shmouni, Fady, Rachel Morissette, Ninet Sinaii, Meredith Elman, Toni R. Prezant, Wuyan Chen, Ann Pulver, and Deborah P. Merke. "Revisiting the Prevalence of Nonclassic Congenital Adrenal Hyperplasia in US Ashkenazi Jews and Caucasians." Genetics in Medicine 19, no. 11 (November 2017): 1276–79. https://doi.org/10.1038/gim.2017.46.
  • Miller, Walter L. "Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol." Hormone Research in Paediatrics 91, no. 6 (2019): 416–20. https://doi.org/10.1159/000501396.
  • Gardner, David. Greenspan's Basic and Clinical Endocrinology, Tenth Edition. McGraw-Hill Education, 2017.
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  • Goodman's Basic Medical Endocrinology, 2022. https://www.clinicalkey.com/dura/browse/bookChapter/3-s2.0-C20170018724.
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