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0:11
So it's a great pleasure now to discuss with you endocrine diseases in Carney complex.
0:22
You probably know this paper that is the first description of what we call now, Carney complex. This paper is now 40 years old. But you have to realize that 40 years, to describe a disease, that’s quite recent, in fact. And when Dr. Carney, was as you probably all know, a pathologist at the Mayo Clinic, described the disease and identified the disease, he started by the description of four patients from the Mayo Clinic, that were reported one year before this paper, as presenting
1:04
a very unique cause of Cushing's syndrome, so of cortisol excess, that he called primary pigmented nodular adrenocorticol disease or PPNAD. And... later on he realize that these patients are similar cases in the literature and similar cases in the Mayo Clinic archives, that presented with other manifestations. And he had a very smart idea to make the hypothesis that there was a link between PPNAD and these other manifestations. And among these manifestations he noticed
1:42
spotty brown black pigmentation of the skin, that we know now as... periorificial lentiginosis. So small pigmented spots around the eyes and around the lips, and myxomas. And especially myxomas so that are located in the heart. So cardiac myxomas. And, these three entities that he grouped around this term complex of myxomas, spotty pigmentation, and endocrine overactivity, is what we call now Carney complex, after him. And I'm going to describe today the endocrine aspects.
2:27
so what he called at that time, endocrine overactivity.
2:32
Just to illustrate, this quite unique cause of Cushing's syndrome, PPNAD. And you can easily understand that, as a pathologist, Dr. Carney was, very intrigued by this aspect. These are two adrenals removed from patients from our Center. Patients suffering from Cushing's syndrome, due to PPNAD. These two adrenals, they have a normal size and normal weight. But what's unique is this small nodules that are highly pigmented. You can see they are less than one centimeter, you have here the scale.
3:11
And this is quite unique, if you look at the aspect of other causes of Cushing’s, for instance adrenal cancer (ACC), or adrenal adenomas (ACA) or another form of bilateral nodules that we call primary bilateral macronodular adrenocorticol hyperplasia (MACRO). Where the nodules are much larger, more than one centimeter. And we realized recently, that this is also a genetic disease. But it’s diagnosed in adults usually between the age of 50 to 60. Nothing in relation with PPNAD,
3:46
that we are going to discuss today. The gene of Carney, as you all know, has been identified by my friend and colleague, Dr. Stratakis, now 25 years ago, and with his postdoc, Dr. Larry Kirschner. And we were very interested to realize that the gene that Stratakis identified, was sitting in the PKA cyclic AMP signaling pathway. As you all know, this is the regulatory subunit, R1A, of the Protein Kinase A enzyme. And this signaling pathway plays a key role in various endocrine cells,
4:30
especially, for instance, the adrenal cortex, where pituitary ACTH stimulates cyclic AMP and then PKA signaling. And the genetic defect, that causes Carney complex, activates the PKA. So mimics somehow the effect of the stimulation of the pathway. And we know that there are several endocrine glands where the signaling pathway is key for development, for maintenance, and for hormonal regulation, hormonal secretion. And this is, for example, the case in the pituitary for the growth hormone cells.
5:12
The case for the thyroid cells, that are stimulated by TSH. The case, as I already described, for the adrenal cortex stimulated by the ACTH. And the case for the gonads, so ovaries and testes, that are stimulated by FSH and LH that in turn secrete estradiol and testosterone. As the adrenal cortex will secrete cortisol. As the thyroid we secrete thyroid hormones. And as the pituitary, after stimulation by GHRH, that stimulates PKA, will secrete growth hormone.
5:49
We have three different series of patients that have been reported in the literature that I take an example just to describe the various manifestations of Carney complex. And you probably are all aware of these studies. The first one is the initial description by Dr. Carney, 40 patients. The second one is a study that we done in collaboration with Dr. Carney and Constantine Stratakis, is the retrospective analysis of a large series of patients with Carney, that have been genotyped at the NIH
6:26
or later on in our Center for European patients in Cochine Hospital. And the last one is a more recent prospective study that we’ve done at the national level, where we’ve followed for three years, once a year, the patients that were enrolled, for all of the manifestations of Carney. And, in red here, are pointed the endocrine manifestations: PPNAD, thyroid tumors, Acromegaly, so growth hormone secreting adenomas, ovarian lesions, and testicular tumors.
7:04
We are going to describe these various manifestations. By PPNAD, Cushing's syndrome, the main manifestation that led to the description of Carney complex. So a few others. But the adrenal, for the one that would be less familiar with this endocrine gland, this is a very small gland, localized above the kidney.
7:26
You can see the on this CT scan.
7:31
And, you can see this gland, after removal by the surgeon, and removal of the fat by the pathologist. Because the gland is surrounded by fat, as you can see here. And when the pathologist cut this... gland, you would see that there are two different zones. One in the center that we call the medulla, that is not altered in Carney complex. And one surrounding it, a little bit yellow because it’s lipid rich, that is the adrenal cortex. The adrenal cortex makes cortisol, aldosterone,
8:12
and the androgen DHEA. And this is the adrenal cortex that is altered in PPNAD. And pigmented nodules arise from the adrenal cortex. And they over secret cortisol. The other hormones are not altered in most patients with PPNAD.
8:36
The adrenal cortex is controlled by the pituitary hormone ACTH. And the cortisol, when stimulated by ACTH, would in turn, inhibit the pituitary axis to avoid too much cortisol to be secreted.
8:55
In normal subjects, when the corticotrope axis works fine, there is a circadian rhythm where cortisol levels would be high in the morning and low in the night. In Cushing’s, regardless of the cause, PPNAD or other causes of Cushing's syndrome, because PPNAD is one of the various causes of Cushing's syndrome, there is a loss of the circadian rhythm, so in the night, the cortisol remains as high as it is in the day.
9:30
And we know that the cortisol acts on various tissues because the receptor of the cortisol, the glucocorticoid receptor, is quite ubiquitous. So it acts on the adipose tissue, on the bone, on the liver, on the muscles, on the pancreas, on the brain, on the local side. So it has ubiquitous action. So we can easily understand that when
9:58
a patient suffers by an overproduction of cortisol, cortisol excess, in the most severe cases, they might present with many manifestations: thinking disorders, vascular and heart disease, hypertension and diabetes, increase in body weight, myopathy, sensitivity to infection, osteoporosis and so on.
10:30
Because PPNAD, as we will see later, is diagnosed mostly in children and young adults, it's quite often, that it could be observing a child. And cortisol excess in a child will alter growth. And you have here one example to illustrate that. These are two twin sisters. One, as you can guess, the upper one, suffered from Cushing's syndrome. This is not PPNAD, this is another cause of Cushings, but the consequences are the same. It’s Cushing disease.
11:07
After treatment, and in this case this is pituitary surgery. Bone density improved And as you can see, she recovered a normal appearance as her twin sister. But if you look at the whole body picture of them, they are ten years old here. When they are 15 years old, you can see that the one who had suffered from Cushing’s Because during Cushing’s, before the diagnosis and the treatment she stopped growing. Then she didn't really recover at the end. So even though she's fine, apparently,
11:47
and doesn't suffer anymore from manifestations of Cushing’s, there is a sequela at the level of the bone. The fact that the growth failure, before the treatment, was not able to catch up. And this is one thing to keep in mind that with Cushing's syndrome: the younger the patient, the most favorable, usually, is the outcome after cure. Because patients are going to recover from hypertension, diabetes, body weight increase, much better if they are younger than older.
12:24
But there is one thing that cannot catch up in all the patients. When the consequences of cortisol excess on growth have been too severe, this is the final height. So this is one thing to keep in mind, where we are going to discuss later on, treatment of Cushing’s. I won’t recommend the same attitude in a child with severe growth failure than in an adult with just only body weight increase and hypertension, for instance. The age of diagnosis. So this large cohort
12:56
that we analyzed in a retrospective way with Dr. Carney, that you see here, my friend Constantine Stratakis, and this is a picture that was taken in the Azores. So an island in between Europe and the USA, that... this smart, Portuguese endocrinologists thought it very appropriate to organize a meeting on Carney complex. And we met there with him, and a family that he takes care of on the island, with Carney complex. And this was a very nice occasion to discuss
13:31
with the Dr. Carney and Constantine about the cohort. And as you can see, the age at diagnosis. The first, the youngest patients are around 4 to 5 years old. And after the age of 15 to 16, there is an increased prevalence of females. That's the age at diagnosis. There is an overall female prevalence, where you will have 2.4 female for 1 male. And this is occurring after puberty. Leading to the speculation, but we don't have yet full proof of that, that sex might play a role
14:12
in the development of the disease.
14:16
Just to illustrate the situation, here are the main facts about Cushing's syndrome in the first five patients that we diagnosed when the gene was identified by Constantine Stratakis, as having a Carney complex gene mutation, and no other manifestations of Carney then PPNAD. And you can see, most of them are female. There's one male of the five. The age at the first reported symptom varies between 5 and 27 years old. But the age of diagnosis, in most cases, is much later.
14:59
There is clearly a diagnostic delay. This can be explained by many different hypotheses, but one is that in these patients, 3 out of 5 of these patients presented with cyclic attacks of hypercortisolism. And it means that there are periods where they made too much cortisol and then it's normalized. And the time to have the appointment with the endocrinologist, if someone would speculate about Cushing’s, maybe long enough that when they see the patients, there is
15:34
not anymore in active Cushing's syndrome and the biological investigations are normal. But usually it comes back later, and after some time, some months or some years, depending on the patient, it's constant, and then the diagnosis is made. So this is one, first explanation. The other of course, is that as for a lot of rare disease, the physicians are not always aware. so they are not thinking about the diagnosis. But things are improving with time I think, at least the last 20 years. And also
16:05
with the help of internet, I would say, because patients, more and more now, are themselves thinking about the possibility of Cushing’s. As you can see, when the diagnosis was made they all have very high urinary free cortisol levels, especially the ones that are young kids. This is unusual to have such high levels when you are ten years old, And they all had, at the time of the diagnosis, a complete loss of the circadian rhythm because the plasma cortisol in the morning and evening were
16:35
clearly the same. ACTH is completely suppressed because cortisol exerts negative feedback on the pituitary. And as you can see, one presented with adrenal nodules but the other one present a normal CT scan. This is another explanation why the diagnosis, sometimes, when people that are not aware of the disease, it is difficult to make because you have biological proof of adrenal Cushing’s but no adrenal tumors. And if you don't think about PPNAD, where the nodules can be so small
17:07
that you don't see them on the CT scan, you might not think about the possibility of the diagnosis. Here’s one example of the six week aspect of cortisol excess in an 11 year old girl that, collected salivary to assay cortisol every day, 17 consecutive days, in the morning and in the evening. As you can see, it's high in the first,
17:35
8 to 9 days. And then it's in the normal range for the morning cortisol, but what was still abnormal is that the night cortisol is at the same level as the morning cortisol. Right? Should be much lower than the morning cortisol. So it's cyclic. But if you look carefully, there are stigmata of cortisol dysregulation in these patients.
17:58
As I said, the CT scan can look normal or almost normal. So if you don't know this disease you might miss it.
18:08
And how often PPNAD is observed in Carney complex. Here’s the results of our perspective study in France where before inclusion, 40% of the patients were already diagnosed with PPNAD, and at the end of the three year follow-up, that's 57% with overt Cushing’s that deserve treatment. What we observe in this cohort is that, with systematic screening, patients might present abnormalities of cortisol, especially an abnormal dexamethasone suppression test. While they don't have yet
18:51
clinical signs of Cushing’s, and their urinary and midnight cortisol might be still normal. So they have cortisol dysregulation, but not
19:03
bona fide Cushing's syndrome, or maybe not yet bona fide Cushing's syndrome. So we monitor them carefully. And some of them, with time, two or three years later, develop overt Cushing’s and then started to be treated.
19:21
PPNAD is clearly one of the most frequent manifestations of Carney complex. And one of the... and clearly the most frequent endocrine manifestation of Carney complex.
19:34
The Carney complex gene, we know that that there are some mutations that predisposed mostly to PPNAD and the patients do not present with the other manifestations of the disease. This is the case for this specific mutation here. That is a small deletion in an intron of the gene, that is highly prevalent in France. We reported it for the first time, a little bit less than 20 years ago. And in collaboration with Constantine, he was able also to identify the family
20:08
that were referred to him from Spain, another one that was from North America. But the other family at that time were from France. And since that time, we increased the number of index cases of families in France to 15, and we have 51 patients. And studying these cohorts, this is not yet published, but we know that they present with PPNAD, and no cardiac myxomas, no pituitary adenomas, no schwannomas, and no breast myxomas so.... this is one of the rare
20:40
Carney complex mutations that predispose mostly to PPNAD and not the other manifestations of the disease. And why is it so prevalent in France? It is because we think that there is a founder effect in the north of the country, even though each family has a different family name. And so if there is a common ancestor, it's more than 3 to 4 hundred years ago. But most of the patients, they come from the north of the country. And we have families now that are referred from
21:08
the French speaking part of Belgium. So the country that is just at the north border of France, so close to the French families that were identified. There is another gene that can cause only PPNAD. This is the catalytic subunit of PKA. This is much more rare than mutations of the Carney complex gene. This is not a mutation, but a duplication of the gene. We have identified now 15 patients from 7 families in France, and few of them also from Brazil. And... studying here again the phenotype,
21:44
they don't present these other tumors. They might present testicular tumors, ovarian lesions, thyroid tumors, and lentigines but not the other ones. So this is important for patient information and of course, monitoring.
22:02
So in conclusion about PPNAD, bilateral pigmented micronodules that are smaller than one centimeter. The diagnosis is usually between the age of 5 to 40. It’s more rare later. It's very rare before five, but it can happen. It can be cyclic. It can be initially, and this is clearly what we see with familial screening, without clear clinical signs of Cushing’s. But at the time of diagnosis in the case was not in the situation of a familial scanning,
22:35
there are usually clear clinical signs of Cushing’s with major biological alterations as you saw in the series of five patients I mentioned earlier. CT scan can be normal or can demonstrate micronodules that the clinician is not always sure that this corresponds PPNAD because when it's small, it's difficult to be confident about that. The treatment, so the classic treatment is bilateral surgery. Some patients have been treated with unilateral adrenalectomy with good success,
23:12
but they, I would say, are the exception. We have limited experience with anti-cortisol drugs. We start to do it mostly with the patient with no clinical signs that are identified by familial screening. It’s worked well. But we don't know yet if it will work for lifelong and if it will be enough. And I would recommend that only in patients with minor clinical manifestations, and not in a case with a dramatic growth failure, because you might then lose the opportunity to catch up
23:45
with the growth by a potent treatment. Today, the genetic cause of Carney can be identified in more than 80% of the patients. And even in the patients with isolated PPNAD, combining R1A sequencing, and search for C alpha duplication, it's more than 60% of the patients with isolated PPNAD that can present with genetic explanation. Let's discuss now,
24:19
the pituitary manifestations of Carney: pituitary adenoma and Acromegaly. So the pituitary gland is depicted here, and it's made of the posterior lobe and anterior lobe. What's altered in Carney complex, or can be altered in Carney complex, is the anterior lobe. The anterior lobe contains various cells. The cells that make ACTH, FSH, and LH, TSH, growth hormone, and prolactin. The one that can be altered in Carney’s is growth hormone, and in a subset of patients, the prolactin secreting cells.
25:01
Growth hormone, when secreted by the pituitary, in the general circulation, stimulate at the level of the liver the production of IGF-1. And act, as well as IGF-1, on various tissue like the bone, the muscle. Of course, the main effect of growth hormone in physiology, is to stimulate growth in children, but it has many other effects, both in children and adults considering the fact that there are many tissues that express both the growth hormone and the IGF-1 receptor.
25:36
Excess of growth hormone can lead to many manifestations. And this is what we call the Acromegaly. Acromegaly means in Greek, large extremities large hands, large feet, because that's the effect on the soft tissue of the growth hormone that increases the volume. It leads also to change in the facial appearance, with facial deformation. It increases volume of the heart, of the liver. It's a cause of hypertension and also cause of diabetes like cortisol excess. Prolactin acts, physiologically,
26:19
on the mammary gland to stimulate milk production. When prolactin is too high, it can inhibit also the gonadotropin cells. So it inhibits FSH and LH, it decreases the activities of the ovaries and the testes. It can cause galactorrhea, so that means milk production, gynecomastia, that means breast enlargement in male. And it can, of course, decrease both estrogen and testosterone in girls and boys, male and female respectively, causing hypogonadism, irregular cycles, and amenorrhea.
27:01
Acromegaly is diagnosed in Carney, as you can see from the large cohort that we have and this research was done by Dr. Carney and Constantine Stratakis. Usually in young adults, it's very rare in children.
27:17
By our systematic screening, in our prospective study, we observe that 9% of the patients were diagnosed with Acromegaly before inclusion in the study. And at the end, because they all had systematic screening with growth hormone and IGF-1 assays, that was 19% of the patients. And as for cortisol, there is a subset of patients with alterations of growth hormone and IGF-1 that do not match the diagnostic criteria for Acromegaly. But that's true that there is some level of
27:53
hyperactivity of the axis, even though they don't have bona fide Acromegaly And that's observed in a third of the patients. It’s quite significant. And in this cohort that’s only two patients that present with increased prolactin. So increased growth hormone is more frequent than increased prolactin What’s happening in Carney complex pituitary is a hyperplasia or some small adenomas. As you can see here in this patient, that was published from NIH neurosurgeon, was a very small microadenoma.
28:26
And sometimes you can have a large adenoma. So in conclusion, just 12-20% of the Carney complex patients that develop classic Acromegaly that deserve treatment, usually after the age of 20. Patients with pituitary hyperplasia are not going to be cured by surgery. Patients with microadenomas, maybe, but it really depends on the number of the morphological presentations. And there are rare patients with microadenomas that will deserve surgery. So at the end of the day, probably,
28:58
we treat less by surgery Acromegaly in Carney complex patients then in other types of patients with Acromegaly. They do medical treatment which is somatostatin analog and growth hormone receptor antagonist. And there is a subset of patients with somatotroph axis dysregulation, some level of hyperactivity, that is, from the clinical point of view, today, the significance of that is not known. We might speculate that this might be... on the development of some other manifestations of Carney,
29:34
so this is something to keep in mind. Let's discuss now, thyroid nodules. So usually, despite the fact that cyclic AMP stimulates production of thyroid hormones, the thyroid hormone levels are normal in Carney complex patients. A few patients have excess of thyroid hormone but because this is not so rare in the general population, I'm not convinced that this is due to Carney. but thyroid nodules are most frequent in Carney complex then in the general population.
30:07
It's already quite frequent, as you know, in adults in the general population. It’s more frequent in Carney. That’s 11% to 35%, depending on the criteria. The more stringent the criteria would be in terms of size of nodule, it would be closer to 11%. But if you are less stringent, it's about a third of the patients. And considering that they are young adults, it is more than the general population. In the old population, it would be not that different.
30:31
What is clearly different then the general population is the frequency of thyroid cancer. This is 2% in Carney complex which is some what not very high. You're pretty good. But this is more than the general population. As you can see, thyroid tumors in Carney complex occur at an older age then the other manifestations, around 40 years old.
30:54
Let’s discuss now, to finish, testicular and ovarian lesions. Let's start by the testes. The classic manifestation of Carney in the testes are Large Cell Calcifying Sertoli Cell Tumors (LCCSCT). They are bilateral and multiple calcified tumors, as you can see on ultrasound. They are small. They are observed in a third to half of patients, depending on the series. And they are not associated with hormone alteration. So in the majority of the patients, we just monitored them. Certainly if
31:33
there is a growth of this of calcified tumor, then we are going to discuss biopsy or surgery. There is a small subset of patients that present with a different type of tumor developed from the Leydig cell, the ones that make testosterone. And they are secreting estrogen, so it can be a cause of gynecomastia. In the French cohort, that’s
31:57
a series of 26 patients that we have recently reviewed, testosterone, FSH, and LH levels are normal except in one case. So these tumors, except the Leydig ones, that are more rare, are not associated hormonal dysregulation. There is a question mark whether this calcified tumor might alter spermatogenesis. And there are indeed some case reports of infertility. It's difficult to know for sure. We have not done a systematic sperm analysis. And what we know from our cohort in France, is that
32:34
half of the adults had at least one child. One needed in vitro fertilization because this is one of the cases with Leydig cell tumors that was operated on. So... he needed in vitro fertilization. And for the other half, it's unclear whether they are infertile or just they didn't wanted so far to have children. So, the message is that we are not sure whether clearly there's, sperm production alteration, but it should be mentioned and explain to you, men,
33:12
so that probably they would have sperm analysis and, even if they don't want yet a child, it’s probably safe to go to the sperm bank to store the sperm, in case later on the position would be altered. What about the ovarian? So there are an increased frequency of ovarian cysts. There are discussion whether a solid tumor might be more frequent in cancer. I remember discussing that with Dr. Carney, he was not convinced. One thing that... makes it difficult to claim
33:47
that there is an increased frequency of tumors of the ovaries in Carney is that by difference with males, where clearly there is one specific type of tumor, this Large-cell calcifying Sertoli cell tumors (LCCSCT). In females, the histology of the one that had been operated, because they had a solid tumor has various histologic types. And the frequency and the fact that there are various types make that less likely that this is clearly linked to Carney. But this is good practice
34:19
to monitor with ultrasound, ovaries in Carney complex patients. You have to be aware that breast lesion are frequent. Most of them are benign, fibroadenomas and myxomas. They are sometimes difficult to diagnose, if they are not well aware of the disease. And mammography, ultrasound and especially MRI need to be carefully analyzed. And, according to an analysis that we have done in France, there is a slight increase of breast cancer in young Carney complex female patients
34:53
by comparison with the general population. It’s already quiet frequent in the general population, but slightly more frequent in Carney complex. The good news is that these are estrogen positive receptor tumors of good prognosis. We have no case of fatality so far. And they have been all cured. Even the one that was metastatic at the time of the diagnosis. Probably due to the fact that they are positive for estrogen receptor. So what we advise in the country now,
35:23
is to start screening for breast cancer earlier then what we do in the general population. The general population is usually around 50. And we recommend to start somewhere between 35 and 40 in Carney complex patients. So in conclusion, the most frequent endocrine manifestation of Carney is adrenal Cushing’s with PPNAD. It needs to be screened both with clinical examination and biological monitoring, at least once a year, I would say. Then you have growth hormone dysregulation.
35:59
That needs biological monitoring less frequently. It's usually not observed in children. And then you need also to be aware of the presence of thyroid nodules and a slight increase of thyroid cancer. So you need to monitor with ultrasound. And if there is any doubt on the nodules to do a cytological puncture and alteration for cyto-biological examination. And to monitor the gonads with ultrasound, especially in males. I will thank you for your attention. I will just thank my collaborators,
36:37
and our research teams in our clinical departments and all our collaborators at the national level, the European level, and our long term collaboration with Constantine Stratakis at the NIH and in Greece. Thank you for your attention.
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