We review the causative enzyme defects, presentation, evaluation, and prognosis for neonates with congenital adrenal hyperplasia. We are joined by Ming Yang, MD, Assistant Professor of Pediatric Endocrinology at the University of Texas Southwestern Medical Center.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern Newborn Nursery. Welcome back to the podcast. In today's episode, we'll be discussing congenital adrenal hyperplasia, or CAH. We are recording remotely today due to the ongoing COVID pandemic. We are joined by Dr. Ming Yang, Assistant Professor of pediatric endocrinology at UT Southwestern.
Dr. Ming Yang:
Hello?
Dr. Neeta Goli:
Hi, Dr. Yang, thanks for joining us today.
Dr. Ming Yang:
Yeah, thanks so much for having me.
Dr. Neeta Goli:
Congenital adrenal hyperplasia caused by a 21-hydroxylase deficiency is a leading cause of ambiguous genitalia in a genetically female infant and can often include life threatening salt wasting and adrenal crisis as well. If you remember back to med school, it's caused by a defect in the steroidogenesis pathway. To start off with, Dr. Yang, please can you refresh our memories on the adrenals, their function, and the defects that can cause the different types of CAH?
Dr. Ming Yang:
Yeah, absolutely. As a quick refresher, the adrenal glands are suprarenal glands that are composed of two different parts. You have the adrenal cortex and the adrenal medulla and these glands are surrounded by an adipose capsule that forms a protective layer. The cortex is the outer part of the gland and that can actually be broken down into three different sections. First you have the zona glomerulosa, which makes aldosterone. The second part is the zona fasciculata, that makes cortisol. And then the last part is the zona reticularis, which makes the sex steroids. We may or may not have learned the mnemonic in med school of the deeper you go, the sweeter it gets. That's kind of a quick way of trying to remember the different parts of the cortex.
Dr. Ming Yang:
The adrenal medulla is the inner part of the gland and that produces catacholamines, epinephrine and norepinephrine, as well as dopamine. There are a whole bunch of different enzymatic defects that can cause CAH. Just a quick reminder about that, cholesterol serves as the substrate for all your steroid hormones and steroidogenesis actually requires this coordinated regulation with cellular uptake and transport and then the use of the cholesterol followed by a series of unique biosynthetic steps. If you have any type of defect in any of the enzymes that are necessary in these steps, that can lead to the different types of CAH. Knowing the adrenal steroid pathways really kind of helps us figure out the different forms of CAH. They are all passed on in an autosomal recessive pattern, and 95% of CAH cases are actually due to 21-hydroxylase deficiency.
Dr. Ming Yang:
There are a whole bunch of other forms, but they're much more rare and those include, just kind of going top to bottom on the pathway. You have lipoid hyperplasia, which is secondary to a defect in StAR which is steroidal transport acute regulatory protein. Then you have 3-beta-hydroxysteroid dehydrogenase deficiency. Then the 21-hydroxylase deficiency and also 11-beta hydroxylase deficiency. Kind of going the opposite direction on your steroid pathway, you can also have defects in 17-alpha-hydroxylase or 17,20-lyase deficiency. And then there's another one that's kind of a combination of a couple of them, which is p450 oxidoreductase deficiency. It's really important to note that there can also be partial enzyme deficiencies and more mild deficiencies as well. And so this can definitely cause a pretty wide spectrum of disease.
Dr. Neeta Goli:
Along that spectrum, how often are infants with CAH also affected by the adrenal insufficiency?
Dr. Ming Yang:
Yeah, so this question is a little bit tough to give you kind of a finite answer to, because of that spectrum. In the classic forms of all the different enzyme deficiencies that cause CAH, there should theoretically be an inability to form cortisol. However, the ability to form aldosterone and therefore the chance that infants with CAH will actually have salt-wasting crises, really kind of depends on the enzyme defect. For example, kiddos with 11-beta hydroxylase deficiency and 17-alpha-hydroxylase, 17,20-lyase deficiency, do not actually have any salt wasting. And then within 21-hydroxylase deficiency, there are actually three different categories of CAH. First you have your kind of most severe form, which is the salt-wasting or what we like to call classic. The intermediate form is simple-virilizing and then the least severe form is called a non-classic or late onset. There's actually a much higher prevalence of non-classic CAH than the classic salt-wasting form and simple-virilizers and non-classic kids actually do not have any adrenal insufficiency.
Dr. Neeta Goli:
If those are caused by the same genetic defect, what causes the difference in the phenotype between those three?
Dr. Ming Yang:
There's definitely different introns and things that can cause the different ones. And actually, if you have kind of two different issues, the milder form will basically be the more dominant form. It really kind of depends on what is missing on the actual 21-hydroxylase part.
Dr. Neeta Goli:
Okay. I see. And then one other important thing for us to note is that we usually think about CAH causing females to become virilized. It can also affect males, and they might not have the obvious findings of virilization on physical exam. Screening for CAH is included on the routine newborn metabolic screen, which is really vital for early identification of affected babies, especially those who might have more subtle physical exam findings. Can you talk a little bit about how we screen for CAH?
Dr. Ming Yang:
Yeah, so also, I want to be clear here in this context that we're again, kind of honing in on that 21-hydroxylase deficiency, because that makes up again, 95% of cases of CAH. Actually in some of the other forms of CAH, boys can be actually under-virilized, but you're absolutely correct in saying for those with 21-hydroxylase deficiency, boys will have no obvious virilization on an exam. They're just going to look like little boys. For girls, it's important to look for any signs of virilization and feel for the absence of any testicles. The newborn screen actually only screens for 21-hydroxylase deficiency. It doesn't screen for any of the other enzyme defects. What happens here in Texas is that there's actually a two-tier testing strategy. We also actually do two screens in the state, which most states don't do. We end up picking up very early, a lot of the non-classic patients.
Dr. Ming Yang:
What the state does is that it takes the blood spot on the filter paper from the newborn screen and it's screened for 17-hydroxyprogesterone or what we like to refer to as 17-OHP. And this is the precursor that's actually elevated in 21-hydroxylase deficiency. On that first screen, what they do is they'll take the top 5% of newborns, which they're saying are less than seven days old and then they'll also take the top 3% of the follow ups who are greater than or equal to seven days old. And they retest that 17-OHP level. Then out of those that are retested, they'll take the top 20% for the newborns and the top 15% for the follow ups with a certain cutoff for that filter paper 17-OHP level. Additionally, if the child is a low birth weight child, then there's kind of another cutoff that they use for that filter paper 17-OHP. And then, so these will then trigger a second-tier test, which will run the sample through a liquid chromatography tandem mass spec assay.
Dr. Ming Yang:
Those that are elevated on that second-tier test is what comes back as a positive on the screen. When the general pediatricians in the community and the nursery or the neonatologist in the NICU are getting notified of that abnormal screen for CAH, that's the process that triggers the abnormal screen. And if the screen comes back positive, it's going to ask the practitioner to order a serum 17-hydroxyprogesterone and electrolytes. And so, just something to quickly note for you guys who are ordering it, make sure that we're actually ordering the 17-hydroxyprogesterone and not accidentally ordering the 17-hydroxypregnenolone, which is actually a precursor that's elevated above that in 3-beta-HSD deficiency.
Dr. Ming Yang:
The other thing I would do is just kind of make sure that we're doing a really thorough physical exam, specifically looking at the genitalia and then asking the parents to see if there's been any signs of vomiting or dehydration and taking a good look at vital signs and whether the baby's been gaining weight appropriately.
Dr. Neeta Goli:
Okay. With the newborn screen that you mentioned, how often are we finding CAH?
Dr. Ming Yang:
Yeah. Based on kind of neonatal screening and national case registries, the worldwide incidence that's stated in most studies is somewhere between one in 14,000 to one in 18,000 births. Of course the condition is definitely more prevalent in small genetically isolated groups with smaller gene pools. Here in Texas with data from our newborn screening program from 2016 to 2018, our incidence rates for a classical CAH, which what they categorize salt wasters and simple virilizers as classical, was about one in 12,500. And within the US population actually for non-classic CAH, there's a pretty high frequency. It's about one in 200 actually.
Dr. Neeta Goli:
Wow. That's much more common than I had realized.
Dr. Ming Yang:
Absolutely. Yeah.
Dr. Neeta Goli:
Good to have that on our radar. For these babies, how would we expect them to present? I know you mentioned this briefly a bit earlier, but if you can let us know some more details.
Dr. Ming Yang:
Yeah, sure. Again, that really kind of depends on the severity of the deficiency. Non-classic patients will behave completely normally and they'll really present later on in life with signs or premature adrenarche. You'll see usually kind of increased linear growth, possibly some body odor and/or pubic or axillary hair, and some are completely asymptomatic, and kids will present as adolescents or even adults when they come in for kind of irregular menses or infertility evaluation. Simple virilizers also for the most part behave like normal newborns, but they're more likely to have some sign of virilization on exam. For girls, there could be some clitoromegaly or posterior labial fusion, but most of these kids really have pretty normal cortisol production. And so they can also present later on in life, like the non-classic patients.
Dr. Ming Yang:
Salt-wasters or the classic, the true classic form of the disease can actually also behave completely normally until about day five to 14 days of life. Of course, unless they're girls and have ambiguous genitalia, which will tip you off beforehand. But for a boy, they could be totally fine. Adrenal crises are usually going to happen kind of actually that second week of life. And they can present with lethargy, vomiting, dehydration, and shock, and then they can have hyponatremia and hyperkalemia on their labs. Thankfully because we do that newborn screening, we usually don't see this anymore because the screens come back beforehand.
Dr. Neeta Goli:
Okay. Why is it that they present in the second week with the adrenal crisis?
Dr. Ming Yang:
That's a really good question. I don't actually have a great answer to that. And it might just be that it just takes that amount of time for their cortisol and aldosterone levels to kind of lower back down into kind of a more dangerous category. I don't actually know right off the top of my head why that is that it takes them a little bit longer.
Dr. Neeta Goli:
Sure. But good for us to know when we're following these babies up. And then, so what if we have a baby, one of the virilized forms. We have a baby in the nursery with ambiguous genitalia. What are our next steps in evaluation and management while the baby is still in the hospital?
Dr. Ming Yang:
Yeah. Definitely I would do a good thorough exam and then look through the chart to see if there's any relevant history in the pregnancy or any type of family history. Again, it's kind of an autosomal recessive pattern of passing it on, and then give us a call and we will help you evaluate depending on what you're describing and what we see on our exam. A good place to kind of start thinking about ambiguous genitalia in general is just to try to think of this as either an over-virilized girl or an under-virilized male. And remember, there's certainly a lot of other causes of ambiguous genitalia that are not secondary to any adrenal causes or CAH. And like we discussed, even those with the true salt-wasting form of CAH, usually don't “crash” until later on.
Dr. Ming Yang:
Technically it's not an emergency like in the middle of the night, but that being said, there's always a lot of angst from families. There's certainly urgency to start that workup. At minimum, we're probably going to be asking for a chromosome analysis, a FISH for SRY because that tends to come back a lot faster than the chromosomes and some type of imaging such as a pelvic or an abdominal ultrasound. If we're truly worried for CAH or any adrenal issues, we're going to want to make sure that that cortisol production is okay. We're going to ask for a high dose ACTH stimulation test. With the specifics of those precursors, really guided by your suspicion based on the enzyme defects that we're actually thinking about. And if you are worried for any type of salt wasting then, we're going to ask for lytes, aldosterone, and renin levels during basically at the beginning of the test. And there are a whole bunch of other tests that can be run on ambiguous genitalia. It's just going to kind of depend again on what we see. Not all tests are going to be helpful and it really depends on what the exam looks like.
Dr. Neeta Goli:
How does the ACTH stim test work? Would you mind reminding me?
Dr. Ming Yang:
Yeah, so essentially what that is, is for a high dose test, there's actually two flavors of ACTH stim tests. One, there's a low-dose. And then the second one is a high-dose. You would typically do a low-dose test if you're concerned about central adrenal insufficiency, but if you're worried about primary or an adrenal problem itself, you'll do the high-dose. Specifically for the high-dose, what you're doing is you're going to get a baseline ACTH and cortisol. And again, if we're looking for 21-hydroxylase deficiency, we'll also get a 17-hydroxyprogesterone level at baseline. And then we will give for kiddos that are less than two years old, we'll give a 125 micrograms of ACTH. If you're older than two, we'll give 250. There's another smaller dose for kind of some extreme preemies. We'll give that as a Cortrosyn IV push and then get a 60 minute cortisol and 17-hydroxyprogesterone level. And again, there might be some other labs that we'll throw in there, but that's kind of the basic ACTH stimulation test.
Dr. Neeta Goli:
For a child with 21-hydroxylase deficiency, how would you expect those numbers to look before and after the stim?
Dr. Ming Yang:
Yeah, if you have classics salt-wasting, essentially your cortisol levels will not peak with a delta of 10 and a peak of greater than 18, so you'll have cortisol deficiency, and then the 17-hydroxyprogesterone levels really typically will stimulate up to the 10,000 nanograms per deciliter mark or above. That's kind of what we're looking at. And there's a nomogram for what we kind of look at to help us decide is this kind of a regular kid? A non-classic child versus a simple virilizer? or a salt waster? And there can be definitely some overlap in that, but typically kind of 10,000 mark is more of a salt waster, although I've had some simple virilizers certainly stimulate up to that amount. For simple virilizers, the cortisol, it may not quite get to above 18. Usually it's kind of maybe kind of that 14, 14-ish mark. They usually make pretty decent amounts of cortisol, but it may or may not be completely normal.
Dr. Neeta Goli:
Okay. And then you mentioned earlier when you were talking about all the parental angst completely understandable. How do you usually counsel these parents when you're talking to them before we have an answer?
Dr. Ming Yang:
Yeah. That's always really, really hard. Because families have to figure this out and then it's just a lot of these tests you take a bunch of time for the results to result. What I would say is, tell the families that you're going to get a multidisciplinary team of specialists together to help determine the diagnosis and the plan going forward. And I'd really try to tell them to kind of keep an open mind as far as the sex of the baby, especially if there's any ambiguity involved. I would try to avoid using specific pronouns like “he” or “she” and try to remain as neutral as possible and just refer to the baby as “baby,” until there's more information, avoiding sex assignment until more workup has been done I think is really kind of the best way to go for that, because it's really hard to kind of backtrack. Although it's already going to be hard because if they've already found out the sex of the baby ahead of time, I think it's really difficult.
Dr. Ming Yang:
And as far as advice for PCPs who are kind of counseling parents who have newborns that have abnormal newborn screens for CAH, I do think it's important for the pediatrician to know a few things. The newborn screen usually is going to report that 17-OHP level as either kind of mildly elevated, moderately elevated or severely elevated. And while every newborn screen should definitely be taken seriously, I wanted to highlight, remember that the screen is still just a screen and the point of the screen is to try to pick up as many children as possible so we're not missing any cases. However, when we're trying to not miss any cases, sometimes they can cause a bunch of parental angst, if there were any type of false positives or just more milder forms of the disease. Clearly if you have a severely elevated 17-OHP level, that needs to be kind of dealt with immediately and promptly discussed and coordinated with endocrinology.
Dr. Ming Yang:
And we should absolutely tell the parents the possible severity of adrenal crises. But that being said, if you have just kind of a mildly elevated screen, that could be completely normal and probably more likely to be a non-classic child. It's probably also more likely to be true if only the second newborn screen is abnormal. And I really hate for families to be kind of unnecessarily freaked out. The levels are also a little bit higher in sick kiddos or preemie kiddos. There's actually other, again, other nomograms based on how premature they are and what their birth weight is for the NICU providers specifically. They'll come back with a really high level and really just based on their gestational age, it can be completely fine. Clearly there's always exceptions to every single case, but it is, I think, important to discuss, following up with an endocrinologist. But it's also important to also know that the non-classic kids may never need any type of treatment at all.
Dr. Neeta Goli:
What should we expect long-term treatment and management for the bulk of these kids, both medically and cosmetically?
Dr. Ming Yang:
Yeah. Long-term treatment really kind of depends on the severity of the enzyme deficiency. Like I just kind of talked about, a lot of non-classic patients may not need any treatment at all. Sometimes we will treat if it's causing premature adrenarche or advancement in bone age. For the classic salt wasters, with 21-hydroxylase deficiency, the neonates are treated with not only salt supplementation, but at the very beginning, we're giving them pretty high doses of hydrocortisone to kind of start bringing those levels down as soon as possible. And then we're also giving them fludrocortisone. Over time, we're going to actually take the salt supplementation off and then the kids are basically maintained on hydrocortisone to cover that cortisol deficiency and fludrocortisone for the aldosterone deficiency. For the first 18 months of life, our guidelines kind of recommend seeing them every three months and then kind of thereafter, we push it out a little bit further to every four months.
Dr. Ming Yang:
And what we're medically doing is that we're just monitoring their labs and blood pressure and growth and pubertal progression. And then we adjust their medications as they grow. Their hydrocortisone usually is based on kind of their body surface area and then also what their labs are looking like. The other thing that we are teaching our families to do is basically in times of stress, we teach them to give stress dose on the glucocorticoids. Just higher doses of those. And then depending on their control, the kids may still struggle with premature adrenarche or rapid linear growth and advancement in bone age, which can compromise their final adult height. And some of these kids actually will get triggered into central puberty early so we may need to address that part of things with a different set of medications.
Dr. Ming Yang:
For kids, for boys who are older with CAH, we do monitor for something called TARTS, which stands for testicular adrenal rest tumors, and what these are actually just benign ACTH-dependent tumors that if left untreated, can actually destroy their testicular tissue and then lead to issues with fertility, but these tumors actually respond very nicely to higher doses of medication so really it's just kind of getting that ACTH level down with some additional medicine, should help decrease or make those tumors go away, assuming that they're not already gigantic.
Dr. Ming Yang:
Eventually when they've really finished their linear growth, then what we can do is change their hydrocortisone over to a longer acting glucocorticoid like prednisone or dexamethasone. Usually we're trying not to use those in our younger kids because they're growing. And those other steroids are just much more growth-suppressing. There are some newer experimental drugs that are being developed, as well as kind of improved glucocorticoid delivery methods, such as putting hydrocortisone through a pump, so that could be really exciting for the future.
Dr. Ming Yang:
From a urologic or surgical perspective, what we do is we'll refer the virilized girls over to our urology colleagues to talk about all the surgical options for any type of your urogenital reconstruction that they may need. They'll talk to them about kind of the timing of surgery and if it needs to be any type of staged procedure, different stages and the pros and cons of kind of early versus delayed surgery and/or even observation until the child is older. The type of surgery and that timing is again, kind of best discussed with the surgeon and it's also dependent on probably how bad the virilization is. If those girls are kind of getting a whole bunch of recurrent urinary tract infections and also family preference for the gender assignment and any type of fertility implications for the future.
Dr. Ming Yang:
Adolescent girls who have had a history of being virilized and have had surgeries, they may need continued care with gynecology and or urology, especially if there's any concerns for stenosis or delayed or painful menstrual cycles. And then if they're thinking about starting to have sexual activity, then they may need some things like dilation in the vaginal area. And then eventually if they do want to talk about pregnancy, then that's always a good place to talk with the gynecologist about that.
Dr. Ming Yang:
Long-term, I think it's also kind of important that these patients have access to behavioral and mental health providers to address any concerns related to CAH. We don't really know conclusively what the effects of high androgen levels are on the body and the brain and on gender-related behavior, especially if that happens kind of in utero as well. Nevertheless, studies have actually showed that most female-raised adolescents and adults with 46,XX CAH, end up identifying as female. There was a study of 250 individuals with 46,XX CAH who were raised female and only about 5.2% had any serious gender identity problems. At this point in time, we really kind of lack a bunch of systemic comparative studies of early versus late genital surgery or electing to have no surgery at all in regards to just outcomes of sexual functioning and quality of life.
Dr. Neeta Goli:
That was really thorough. I appreciate all of that guidance. I think you've already addressed this, but are there any other co-morbidities, which you didn't already mention, which the general pediatrician should be aware of while caring for these children later in life?
Dr. Ming Yang:
Yeah, so I just talked kind of briefly about girls that had urogenital anatomy issues, because they do tend to be more prone to having urinary tract infection. I would be on the lookout for that. And kids actually with classic CAH, are more likely to get into trouble and require hospitalization with any type of vomiting illnesses, such as viral gastro or urinary tract infections, especially under the age of two, if they're unable to tolerate their medications by mouth. And if they are needing glucocorticoid therapy at all, just remember that you should recommend for them to stress dose their steroids during any time of illness or with procedures. Again, we teach them how to do that. That's part of their training, but a lot of families either kind of forget or are not particularly good about doing that. It’s always a good reminder if it comes from the general pediatrician.
Dr. Ming Yang:
And then some of these kids can really kind of struggle with obesity as well, because a lot of them do need higher doses of glucocorticoids. So we're kind of trying to balance everything out by kind of trying to control their levels with hydrocortisone but then that can also make things a little bit harder from a weight standpoint. And then, since again, we do the two newborn screens here in Texas, we're seeing a lot of non-classical CAH patients, right from the beginning, who again, we tend to just kind of follow these kids over time and then if they do have any additional issues or their levels get to a point that we worry that they're going to have advancement in bone age, then we may start something. But a lot of the times the families are just like, "You guys aren't doing anything." Then often they will just kind of stop following up with us.
Dr. Ming Yang:
What I would be on the lookout in these kids is, as a general pediatrician, would be to actually look for, again, signs of premature adrenarche and rapid growth. If that were to happen, just say, "Hey, maybe it's a good time to kind of touch back base with the endocrinologist."
Dr. Neeta Goli:
Okay. The importance of the medical home again and working with our specialists. To end the episode today, do you have any last-minute advice for our listeners while they're taking care of newborns?
Dr. Ming Yang:
Well, I would just say, just give us a call if you're concerned for any endocrine-specific things or have any questions about abnormal newborn screens or any labs. A lot of the times we're very friendly over the phone, so we can help you out and help you guys decide if a kid needs to be seen in our clinic or not. And we can also help avoid a bunch of unnecessary referrals and reserve those clinic appointments for kids that really need to be seen in clinic. A lot of the times we just kind of get a whole bunch of referrals and there's so many of them that it often takes quite a bit of time to get in. If it's something that we think that you guys can deal with and we can help walk you through it, then absolutely I think, give us a call. I don't think you'll regret it. It will be beneficial for both of us.
Dr. Ming Yang:
And I just wanted to say, thanks for all that you guys do as primary care physicians, taking care of our patients. We really wouldn't be able to do what we do as sub-specialists, without having you guys as that primary home and that base.
Dr. Neeta Goli:
And we appreciate your expertise and your guidance. Thank you so much for joining us today and for your time.
Dr. Ming Yang:
Yeah. Thanks so much for having me. This was really fun.
Dr. Neeta Goli:
Thanks for listening to Newborn News. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback or suggestions for future episodes, please email me at NewbornNews@utsouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests and do not necessarily reflect the views of the university.