Hi. Today we are gonna 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
and there are five major enzyme mediated steps.
Remember that there’s decrease cortisol,
therefore there’s increase ACTH which is negative feedback.
This leads to overstimulation 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 is 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 nonclassical form of 21-hydroxylase deficiency,
which we'll discuss very soon, was first described by Jacques Decourt,
Max-Fernand Jayle, and Ettiene Baulieu.
CAH has a 1 in 60 carrier rate and occurs in 1 in 5.000 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 a salt-wasting.
And this is a 1 in a 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 is also a predisposition of Sephardic Jews or North African Jews.
They are likely to have a different type of mutation
of the 11-beta hydroxylase deficiency.
And this accounts for 5-8% of all cases.
It occurs in 1 in a 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.
And it’s the most common cause of genital ambiguity
leading to 46,XX genetific females
looking as though they are ambiguous or undetermined genetalia.
Traditionally, this was called female pseudohermaphrodite.
21-hydroxylase is a cytochrome p450 enzyme
that is encoded by CYP21 on chromosome 6p21
which P stands for “petit” 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 would have an input into the adrenals
that will cause an enzyme called StAR,
that will translocate cholesterol into
the inner membrane of the mitochondrion.
Once that occurs, pregnenolone is made.
And pregnenolone usually transform into progesterone.
However, in 21-hydroxylase deficiency,
the progesterone does not become deoxycortisone.
And in this pathway, 17-hydroxy progesterone should become deoxycortisol.
But without 21-hydroxylase, this does not occur.
So as you can see, aldosterone is not made, neither as cortisol.
However, the precursors that would lead to this third arm of the pathway
caused increased 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
and the most severe salt-wasting form of 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.
11-beta hydroxylase deficiency.
So in this pathway, we are able to make it one step further.
However, there is a defect in the enzyme, 11-beta hydroxylase.
So you could see here in the first arm of the pathway,
the deoxycortisol is the last hormone that is made,
but it’s blocked in 11-beta hydroxylase.
So, aldosterone is not made.
You can see here in the second arm of the pathway,
that we're stopped at the 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,
and that actually cause the virilization of 46,XX infants.
So, let’s talk about 11-beta hydroxylase as it presents.
It’s very much less common than the traditional 21-hydroxylase deficiency.
It represents 5-8% 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.
And 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 use for 21-hydroxylase deficiency.
Let’s now review a less common pathway
of congenital adrenal hyperplasia.
This one is 3-beta hydroxysteriod dehydrogenase deficiency.
So you can see here, this occurs high in the pathway
and you actually don’t make
aldosterone, cortisol, or the sex steroids that you should had have.
If you would like to read more about this,
please download the information later on.
Let’s review this clinical presentation of
3-beta hydroxysteriod dehydrogenase deficiency.
It occurs in less than 2% of patients with CAH,
so you’re unlikely to have an exam question regarding this deficiency.
Just so you know the results in
decrease synthesis of cortisol, aldosterone and androstenedione
which makes it different than the others.
There is increase secretion of the DHEA.
DHEA again, is a relatively weak androgen
and 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 crisis.
Remember that salt-wasting in a young infant
can be fatal and should be discovered right away.
Usually the treatment is glucocorticoids, mineralocorticoid replacements with
hydrocortisone and fludrocortisone respectively
as you would do in a traditional 21-hydroxylase deficiency.
Now let us address another deficiency.
17-alpha hydroxylase/17.200 lyase deficiency.
Again, this deficiency causes blockage 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 wanna read more,
you can download the notes associated with this lecture.
So 17-alpha hydroxylase/17.200 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 the ACTH,
which causes increase hypertension, increase hypovolemia, increase hypokalemia.
So hypervolemia is too much blood volume, while hypokalemia is decrease potassium.
You have a ratio of aldosterone to renin that is decreased and you do not have the
female pseudohermaphrodism 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
and 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 would like to keep going, you can skip this but if you’d like to have
more information, I’ll review it now.
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 died very early in infancy
unless there is an astute clinician who can make the diagnosis early enough.
Genetic males become phenotypically females 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 wanna know more information, please download the details.
So what is the treatment of the StAR protein deficiency?
Typically we replace glucocorticoids and mineralocorticoids.
Genetic males are usually assigned a female sex rearing
but this should be discussed in the context of
family with psychologist and therapist on staff to help you assign sex rearing.
Genetic males and females require
estrogen replacement at the expected age of puberty.