Hi. Today, we’re going to discuss congenital adrenal hyperplasia. This is often questioned on your exam.
So make sure to pay attention and I’ll try to keep you awake. Let’s review an introduction
to congenital adrenal hyperplasia. It’s really a spectrum of disorders that have specific enzyme
mutations that can lead to defective steroidogenesis. Cortisol production occurs in the zona fasciculata
of the adrenal. There are five major enzyme-mediated steps. Remember that there is decreased cortisol.
Therefore, there is increased ACTH which is negative feedback. This leads to over stimulation
of the adrenal and over secretion. Let’s talk about the different steroid pathways and the defects
that occur with them. Let’s review adrenal anatomy and physiology. In the zona glomerulosa,
we have mineralocorticoids being made such as aldosterone. The production is regulated by
angiotensin II, potassium, and ACTH. Angiotensin II is abbreviated AGII here.
This function is modulated by dopamine, ANP or atrial natriuretic protein, and other neuropeptides.
The zona fasciculata makes glucocorticoids. Again, this is regulated by ACTH or adrenocorticotropic hormone.
Biosynthesis is influenced by cytokines, IL-1, IL-6, and Tumor necrosis factor.
Neuropeptides and catecholamines are also made in the zona fasciculata. Here, you can see in the image
that there is a cortex represented by C and a medulla which is represented by M.
There’s also a central vein which is represented by V. In the zona reticularis, let’s discuss that,
this is where the adrenal androgens are made. This includes DHEA, DHEAS or DHEA sulfate,
and androstenedione, also some glucocorticoids, cortisol and corticosterone.
Let’s review the history. The earliest documented description of this pathway was documented by
an anatomist named Luigi De Crecchio. In 1957, the mild or non-classical form of 21-hydroxylase deficiency
which we’ll discuss very soon was first described by Jacques Decourt, Max-Fernand Jayle, and Etienne Baulieu.
CAH has a 1 in 60 carrier rate and occurs in 1 in 5000 to 1 in 15,000 live births.
It’s estimated that 75% of patients have this salt wasting phenomenon in which their enzyme
is completely defective. Non-classical 21-hydroxylase CAH is more common. This is a less severe form
that usually is not accompanied by salt wasting. This is a 1 in 100 carrier rate in the New York City population.
Ashkenazi Jews have a distinct predisposition to carriage of this mutation. One in three Ashkenazi Jewish
patients are carriers of the allele and 1 in 27 are actually affected by this disorder.
There’s also a predisposition of Sephardic Jews or North African Jews. They are likely to have
a different type of mutation of the 11β-Hydroxylase deficiency. This accounts for 5% to 8% of all cases.
It occurs in 1 in 100,000 live births in the general population and again is more common in North African
specifically Moroccan Jews. 21-hydroxylase deficiency though is the most common.
It’s the most common cause of genital ambiguity leading to 46, XX genotypic females looking as though
they are ambiguous or undetermined genitalia. Traditionally, this was called female pseudohermaphrodite.
21-hydroxylase is a cytochrome P450 enzyme that’s encoded by CYP21 on chromosome 6p21,
which p stands for petite or the short arm within the HLA region. Phenotype strongly correlates
with the genotype and reflects residual activity if it is a milder mutation. Let’s review now the pathway.
So usually, ACTH will have an input into the adrenals. That will cause an enzyme called StAR
that will actually translocate cholesterol into the inner membrane of the mitochondrion.
Once that occurs, pregnenolone is made. Pregnenolone usually transforms into progesterone.
However, in 21-hydroxylase deficiency, the progesterone does not become deoxycortisone.
In this pathway, 17-hydroxyprogesterone should become deoxycortisol. But without 21-hydroxylase,
this does not occur. So as you can see, aldosterone is not made, neither is cortisol.
However, the precursors that would lead to this third arm of the pathway cause increase in DHEA,
androstenedione, and testosterone leading to the virilization that we see in these children.
21-hydroxylase deficiency again is the most common cause among 46, XX individuals
or female pseudohermaphrodites. Nonclassical congenital adrenal hyperplasia is often in individuals
who are heterozygotes or they carry one normal allele and one abnormal allele for CYP21A2.
Cortisol and aldosterone require 21-hydroxylase for synthesis. Both hormones are deficient
in the most severe salt-wasting form of the disease. 70% of cases of classical 21-hydroxylase deficiency
present this way. Cortisol is not synthesized efficiently. Therefore, the ACTH levels are high.
This leads to the hyperplasia of the adrenal cortex. Again, hyperplasia refers to the increase in cells
and the increase in the gland abnormally. Therefore, there is an increase in precursor steroids
again leading to the phenotype that we see in 46, XX females. Let’s now review
a less common mutation, 11β-hydroxylase deficiency. In this pathway, we’re able to make it
one step further. However, there is a defect in the enzyme 11β-hydroxylase. So you can see here
in the first arm of the pathway, the deoxycortisone is the last hormone that is made
but it’s blocked at 11β-hydroxylase, so aldosterone is not made. You can see here in the second arm
of the pathway that we’re stopped at deoxycortisol. We don’t actually make cortisol
when we have this deficiency. So, we can’t make aldosterone nor can we make cortisol.
However, in the third arm of the pathway, we see that the sex hormones are made. That actually causes
the virilization of 46, XX infants. So, let’s talk about 11β-hydroxylase as it presents.
It’s very much less common than the traditional 21-hydroxylase deficiency. It represents 5% to 8%
of all congenital adrenal hyperplasia. Again, remember that it’s more common in Israeli Jews
in those of North African descent commonly called Sephardic Jews. The patients do suffer
from hypervolemia which means too much blood volume and hypertension. Patients are usually treated
with hydrocortisone in doses that would be similarly used for 21-hydroxylase deficiency.
Let’s now review a less common pathway of congenital adrenal hyperplasia.
This one is 3β-hydroxysteroid dehydrogenase deficiency. So you can see here, this occurs high
in the pathway. You actually don’t make aldosterone, cortisol, or the sex steroids that you should have.
If you’d like to read more about this, please download the information later on.
Let’s review just the clinical presentation of 3β-hydroxysteroid dehydrogenase deficiency.
It occurs in less than 2% of patients with CAH. So you’re unlikely to have an exam question
regarding this deficiency. But just so you know, it results in decreased synthesis of cortisol, aldosterone,
and androstenedione which makes it different than the others. There is increased secretion of DHEA.
DHEA again is a relatively weak androgen. Usually, baby girls are not virilized by the presence
of too much DHEA. Cortisol and aldosterone are not synthesized in the patient and they are prone
to salt-wasting crises. Remember that salt-wasting in a young infant can be fatal and should be
discovered right away. Usually, the treatment is glucocorticoids, mineralocorticoid replacement
with hydrocortisone and fludrocortisone respectively as you would do in a traditional 21-hydroxylase deficiency.
Now, let’s address another deficiency, 17α-hydroxylase/17,20-lyase deficiency.
Again, this deficiency causes blockades high in the pathway which results in no cortisol production
and no sex steroid production. Now, let’s review an uncommon cause of congenital adrenal hyperplasia.
Again, I don’t think you’ll have a question about this on your exam. But in case you want to read more,
you can download the notes associated with this lecture. So 17α-hydroxylase/17,20-lyase deficiency
is a very uncommon cause of congenital adrenal hyperplasia. It occurs in less than 1% of all CAH cases.
The enzyme, recall, is expressed in both the adrenal cortex and the gonads, so that means in the ovaries
or the testes. If the enzyme defect is complete and there is no residual activity,
you will not make cortisol, you will not make androstenedione, testosterone, or estrone.
You have elevation in ACTH which causes increased hypertension, increased hypervolemia,
increased hypokalemia. So, hypervolemia is too much blood volume while hypokalemia
is decreased potassium. You have a ratio of aldosterone to renin that is decreased.
You do not have the female pseudohermaphroditism that we see with 21-hydroxylase deficiency.
But rather, you fail to undergo normal secondary sex characteristics because DHEA and androstenedione
will not be produced. Typically, the treatment for this deficiency is cortisol replacement to suppress
secretion of deoxycorticosterone and thus control the hypertension. Additionally, the patient will usually
require antihypertensive medication. Females will need estrogen replacement
because again, this is blocked and does not occur at puberty as it should normally.
For more information, please download the details. Let’s talk about a very severe form
of congenital adrenal hyperplasia. This is the StAR protein. The StAR protein is responsible
for causing cholesterol to come into the mitochondrion where steroidogenesis actually occurs.
With the StAR protein deficiency, there is absolutely no production of either aldosterone,
cortisol, or sex steroids. Let’s discuss it. It is very uncommon and you’re likely not to see it in the clinic.
You’re also likely not to have an exam question. So, if you’d like to keep going, you can skip this.
But if you’d like to have more information, I’ll review it now. It’s in a less than 100 patients worldwide.
The majority of the patients are of Japanese descent. It’s called lipoid adrenal hyperplasia caused by
mutations in the gene that encode for the StAR protein or steroidogenic acute regulatory protein.
It’s a salt-losing manifestation. Many infants die very early in infancy unless there is an astute clinician
who can make the diagnosis early enough. Genetic males become phenotypically female but with gonads.
Genetic females appear normal at birth but may undergo feminization at puberty with menstrual bleeding.
Progress to hypergonadotropic hypogonadism is very common. This occurs because accumulated
cholesterol will actually kill granulosa cells which are the steroid synthesizing cells in the ovary.
Again, recall this is a very rare cause of congenital adrenal hyperplasia. But should you want to know
more information, please download the details. So, what’s the treatment of the StAR protein deficiency?
Typically, we replace glucocorticoid and mineralocorticoids. Genetic males are usually assigned
a female sex rearing but this should be discussed in the context of family with psychologist
and therapists on staff to help you assign sex rearing. Genetic males and females require
estrogen replacement at the expected age of puberty.