In this talk, pediatric endocrinologist Jennifer Olson, MD, describes how the hormonal processes that lead to sexual maturity are currently understood; provides usable definitions of precocious puberty as well as delayed puberty; and lays out evaluation processes, including how to answer the key question of whether a patient with premature changes is experiencing true early puberty or simply adrenarche. She explains who should get a workup, offers tips to optimize testing accuracy and meaningful results, and clarifies when referral to a specialist is warranted.
And thank you everyone for coming, making time during lunch. Um Let's see. Uh That looks, looks great. Ok, good to go. Thank you. Yeah. So, um, so I adjusted the title slightly to diagnosis, diagnosis and management of puberty that is too early or too late. All right. Ok. Uh I have nothing to disclose. Um, so today I'll try to cover uh these topics, the physiology of puberty, the timing of puberty, the difference between a anarchy and what we call true puberty causes of early and late puberty, how to evaluate early and late puberty and who to refer to an endocrinologist. So, first, I'll just talk a little bit about um, the hormonal regulation of puberty and this is um, a schematic of how um we used to, uh, um, think about uh puberty. Um uh we still do but um, there's more to it. Um, so there's a pulsatile generation of GNRH from the hypothalamus that stimulates the pituitary gland to produce LH and FSH, which then stimulate the testes or the ovaries, um, uh to produce um, uh testosterone uh or estradiol in the ovary. And um, um, and then there's negative feedback, uh to regulate the system. We now know that um there are uh additional higher regulators of puberty, um including um gaba neuropeptide, y glutamate, um leptin ghrelin, um and uh ultimately kiss Pepin, which is what um regulates GNRH. And then more recently, there's um this new morn ring finger protein three which inhibits kiss Pepin. Um So is also a regulator of puberty. So I'll just talk a little bit about um the terms that we'll use gona darky is central puberty. This refers to GNRH stimulation of LH and FSH adrenarche is the onset of androgen dependent changes including pubic hair, axillary, hair, acne and body odor. In females. This is due to the adrenal glands and in males, it can be either adrenal or um hormones from the testes. The lachy is female breast development. Gynecomastia refers to male breast development and monarchy is the onset of menstruation. Um So, the hormones that regulate puberty as um as I just uh showed you include the hypothalamic pituitary gonadal axis and this axis is active at three different time points. Um in the mid fetal um time, the neonatal period and then um in early infancy, um it then is quiet uh during the prepubertal years, generally between ages um two and eight. And then there's an increase in both the frequency and the amplitude of the GNRH pulse generate pulse generator which is uh occurs at the onset of puberty. The adrenal glands start to make D hea s in particular, between six and eight years in both boys and girls. But we usually don't see any evidence of this until a few years later. Um It's important uh when evaluating for early um signs of adrenal activity to have a normal morning, 17 hydroxy progesterone in order to exclude um nonclassic cah growth hormone increases uh during puberty. And this creates a period of insulin resistance and then uh disorders of the thyroid can cause um both precocious and delo puberty. So, it's important to evaluate thyroid function. All right. So the timing of puberty in girls. Um So, uh I have on the right side of the screen, just uh the uh sexual maturity ratings or tanner stages that everyone is familiar with. Um stage one being no uh pubertal development and uh stage five being mature female um development. So, puberty begins in girls when the breast buds reach tanner stage. Uh two and this happens at the same time as growth acceleration. And the um the what we consider to be the normal timing is between ages eight and 13 for the onset of breast buds. Um There's a little bit of a difference in eth uh ethnic groups. Um So um African American girls um almost a year earlier on average um than uh white or Asian girls. Typically pubic and axillary hair occur one and 1 to 1.5 years later. And then peak growth velocity uh occur is occurring between tanner uh breast tanner stage two and three. Monarchy typically occurs between breast tanner stage three and four, which is typically 2.5 years after the onset of puberty. But there's a big range, it can be half a year to up to three years on average and the average age of anarchy uh remains at about 12.5 years. So we are seeing as I, I don't need to tell you, uh we are all seeing this earlier timing of puberty in girls. And um this study from 2010 just compares the percentage of seven year olds with early uh breast development. Um The number in uh or the percentage in 1997 compared with a percentage in 2010. So for white girls, the percentage of uh seven year old girls uh doubled um from 5% to 10% during this time period. Um It increased in um African American girls from 15% to 23%. And then there wasn't any data in 1997 for um Hispanic girls, but 15% in 2010 15% of seven year old, uh Hispanic girls had breast development. Um So we know that we're seeing breast development earlier. Um We know that there is um uh some variation based on ethnicity with African American girls the earliest at an average of 8.8 years. Hispanic girls, 9.3 years average white girls 9.7 and uh similarly Asian girls 9.7. Um however, um it appears that the age of minarchy has remained relatively stable over about the last 25 years, um about four months earlier in African American girl. So 12.2 years on average and then 12.6 years in Caucasian or white girls. Um the age of the Larky, therefore, um and the age of monarchy appear to be less linked uh than they were in the past. And then we also know that um we see uh more signs of early puberty in um in the uh girls who have higher BMIs over 85th percentile. Um So I'll switch and talk a little bit about boys. Um So for boys, um they reach puberty when their testes are uh tan or stage two. So this is either a testicular volume of 4 mL if you're using an uh uh an orca dome or it's measuring using a tape measure. Uh if the long axis of the testee is um more than 2.5 centimeters. So 2.5 to 3.2 centimeters. This um occurs normally between the ages of nine and 14 years. Um That's the normal timing of puberty. Um pubertal onset for boys, um boys uh reach their peak height velocity later in puberty than girls do. So, um girls start to accelerate their growth at the same time. Um as uh breast buds but for boys, they don't reach peak height velocity until they reach Tanner stage three. And then, um, the more uh obvious signs of puberty, voice change, um uh gynecomastia, those those occur even later in puberty towards tanner stage four. Um So there's also been uh a decrease in the age of onset of, of puberty in boys. Um In 1969 the average age of pubertal onset was about 11.5 years. And then um in the early two thousands, um the uh age was about a year earlier for white males and almost two years earlier in African American males. Um So why are we seeing earlier puberty in girls and boys? Well, there's a whole long list of um of things that are being studied and um uh considered um possibilities. Uh definitely BM I um intrauterine conditions and exposures, high meat diets, dairy products, low fiber, um um uh high stress Acti uh decreased activity levels, uh absent fathers, endocrine disrupting chemicals, the microbiome, light exposure, certain hair products, um insulin resistance, geographical location and then um adoption um from developed developing countries to more developed countries. Ok. So what is the definition of early puberty? So even though we know that puberty is starting earlier in girls and boys, the recommendations for um at least considering evaluation haven't really changed. So if girls are showing signs of puberty before the age of eight or boys are showing signs of puberty before the age of nine, we still consider this um to be early, we understand that there's racial differences. Um but we don't want to um miss pathology. So, uh that's one reason for um using these age cut offs, there are different types of early puberty. Central puberty refers to gonadotropin dependent um puberty which is uh LH and FSH stimulation and peripheral uh puberty is gonna add atrop an independent. Um And mccune Albright is a, is probably the most well known example of this um and test toxicosis in boys. Um We also know that examination um and tanner staging can be difficult um particularly determining when a girl has reached tanner two breast stage um and differentiating between um glandular breast tissue and uh fatty uh or lipomas. So when um when you go to evaluate um early puberty, what what I think is really helpful to do is to kind of in your own mind sort out. Is this um patient showing signs of just ad anarchy, which would be pubic hair, axillary hair, body odor acne or are you really um do you really have to worry about um true central um or peripheral uh precocious puberty? And in those cases, you, you can palpate breast tissue you have or you have testicular enlargement um for boys. And then um you determine whether it's central or per peripheral. Um but this is um important because then you're going to tailor your evaluation um to the signs and symptoms that you're seeing? Um So on history, um You'll ask the parent usually when uh when did you first notice the changes? What changes did you see? Um Has there been progression since he first noticed um uh signs of puberty? When was maternal monarchy? Um Does dad remember how old he was when his voice changed? Um Did father um did the dad grow after high school? Was he a late bloomer? Um And then on exam, you're looking for pubic hair, axillary hair, you're looking to see um if uh te the testes are enlarged, you may be uh measuring them. You're looking at the growth curve to see if there's been growth acceleration. And then um you're trying to determine in girls, especially um you know, is that breast tissue um that's glandular or is it fatty tissue. And then you can me use the tape measure um to measure testes. So we see a lot of kids with um isolated premature adrenarche. And again, this is due to the production of adrenal androgens and D hea uh or the sulfate um version of D hea DH es um is in the 10 or 2 to 10 or three range and uh generally in kids who are um uh under the age of eight. Um We see this more often in kids who were born small for gestational age. And then we also know that it is um can be the first sign of um PC OS um that may develop later in girls. So, for these kids, um it's important to exclude nonclassic um cah and uh O or an adrenal tumor. So, the evaluation for isolated premature agen archy is um generally uh looking at ad hea s level. Um and then a morning 17 hydroxy progesterone and a bony X ray. Ok. So, um now we're gonna talk about true precocious puberty, which can again be either central or peripheral. And um so this means that you're either palpating breast tissue in girls or you're seeing testicular enlargement in boys. And if it's central, then it's a gonadotropin dependent process. So you have GNRH activation of LH and of the LH and FSH receptors. And um then also keep in mind that um HCG uh acts on the LH receptor as well. And so, um males, um it's important especially in boys with central precocious puberty or signs of early puberty to measure an HHCG level. Um uh as they can um uh uh tumors producing HCG can um mimic precocious puberty or cause precocious puberty. Um And then in peripheral precocious puberty, you actually have um suppression of LH and FSH uh with elevations in either testosterone or estrogen. And again, this is seen in the MCU and all right Syn syndrome where you have an activating mutation of the GNAS gene um or in test or to which is an activating mutation of the LH receptor. So, um the uh hypothalamic pituitary gonadal axis is active in infancy and um on this um oh I think this, sorry, the little um picture got cut off, sorry. Um But LH and FSH um decline immediately after birth and then they start to rise in the first um after about a month. So in 30 to 60 days after birth, they were they rise to pubertal levels. Um and this results in stimulation of the ovaries or the testes to um produce uh pubertal levels of testosterone or estradiol. They then return to prepubertal levels in girls. It takes about a year, although FSH can be elevated for up to 3 to 4 years and then in boys, they're usually to prepubertal levels by the age of about six months. Um The FSH levels in girls are typically much higher than they are in boys. Um But this, it's important. Um this window of uh looking into the um hypothalamic pituitary gonadal axis is um helpful if you're evaluating um uh babies with either um um optic nerve hyperplasia or um uh different types of ambiguous genitalia um at birth because you can um have this little um temporary uh period of time where you can evaluate their um their hypothalamic pituitary gonadal axis and, and then that gives you tells you um what to expect later on um when it's time for them to go into puberty. So we um see um this commonly um isolated premature, the archy. So this is just uh breast development that usually occurs between the ages of six and 24 months and it is due to this mini puberty of infancy. Um at this age, it's not um due to um maternal hormones. Um, it is important though to, to at least ask about exposures in the home to uh hormone containing medications or creams, um lavender and tea tree oils. Um but this type of um breast development, usually, parents will say sometimes the breasts look bigger, sometimes they look smaller, it seems to wax and wane. Um and then um if there aren't any other signs of puberty, um then usually you can just um provide close follow up. Um but if the breasts seem to be getting larger, if you see other signs of puberty, like pubic hair, then um then you have to uh evaluate further for, for um central precocious puberty or if um the breast uh tissue um persists beyond two years, which sometimes it does and it's, it's still usually this condition. But um at that point, you probably wanna get some labs. So what are the causes of um precocious puberty? And what is um the epidemiology? So, precocious puberty is much more common in girls and boys 4 to 10 ratio to one females to males. It's thought to be um more genetic than environmental. Um We know it's more common if you have a child who was um adopted from a developing country to a developed country. Again, more common in girls and it's more common if there's a history of any type of CNS injury. Um There is some interesting um recent studies on the genetics of early puberty and there is a um has been found um in 9% of central precocious puberty and uh up to 19% in familial central precocious puberty. This loss of function mutation in this morn ring, um finger um three protein. Um So this is inherited from the father um in an autism dominant transmission. And um right now, testing for this is only um in research um uh conditions since the treatment is gonna be the same either way. Ok. So once you've uh decided whether, what type of uh early signs of puberty, um this patient has, then you're going to uh pursue your laboratory um evaluation. So, is it Adrin Archy only um again, isolated pubic hair, axillary hair body odor or are you worried about true central precocious puberty because there's palpable breast tissue or there's testicular um enlargement. Um And then you're gonna go from there. There's um this is a helpful article. It's, it's from a year ago. Um it's in the um journal of Clinical Endocrinology and Metabolism and it's March 2023 and it's um it's uh the approach to the patient with central precocious puberty and it's pretty good, a good review article if you're interested. Ok. So if you are going to um we've already talked about how to evaluate early uh isolated Adron Archy. So now um we're gonna talk more about evaluating um your patient who has signs of a true precocious puberty. So LH is always the most sensitive biomarker um for central precocious puberty. And if you, if you can get a um baseline LH level, that is at least 0.3 units per liter, then you have confirmation on a baseline sample that this is central precocious puberty. Um The important things however, are that it has to be done on an ultra sensitive assay. So, um and it's best if it's an early morning sample. Um and if your level is less than 0.3 it does not exclude central precocious puberty. And this is why we do the um GNRH stimulation testing. So, in early puberty, because of the pulsatile um nature of the um GNRH um pulse generator, you may or may not capture a pubertal LH level on a baseline sample. Um And uh if you don't, it doesn't mean that that your patient doesn't have precocious puberty, it just means that you didn't capture it. The uh again, the test has to be done at a quest diagnostics or a lab core or esoterics. Um uh Our lab uh uh sends all the samples out to esoterics where they're run on a ultra sensitive assay. Um But unfortunately, if your patient goes to Sutter or some of the other um commercial, you know, uh hospitals or labs. Um it, you, you may get a result that just says less than 0.2 and that's not sensitive enough to, to really help you. Um And then depending on if you're evaluating a girl or a boy, you'll want an estradiol or a testosterone level. And then, um again, you wanna make sure it's done on an ultra sensitive assay, uh early morning samples are still the best. And then you wanna be um really mindful of your units. Um So an estradiol level of greater than 15 peo grams per ML is um pubertal at baseline. Um Sometimes you see get an er dial that's uh given in nanograms per ML and then it would be above 1.5. So, um uh the units are important. Um Usually we look at thyroid function and then also keep in mind as uh for boys that HCG can stimulate that LH receptor and um certain tu germ cell tumors can, can present as precocious puberty. So we do um a lot of um generate stimulation testing. This is the testing we do in the day hospital. It takes about five hours. It's um the gold standard for confirming central precocious puberty, especially if you don't get an uh baseline LH level that is at least 0.3 or higher. Um We draw a baseline lhfsh and estradiol. Um the patient then gets 250 mcg of leuprolide as a subcutaneous injection. And then through their IV, they get um lhfsh and estradiol levels drawn at 23 and four hours and an LH level greater than five confirms central precocious puberty on the stimulation test. All right. So, additional um uh evaluation or testing um could be a pelvic ultrasound. So, if your LH is suppressed, but you're seeing lots of estro estrogen and then you have to go looking at the ovaries to see if there um are o estrogen producing ovarian cysts um which is seen in um again, mccune, Albright, which is the constellation of endocrine disorders, polyostotic fibrous dysplasia, and cafe i macules. Um and then um a good uh radiologist can give you uh uterine measurements and ovarian measurements that can um where there are published, published standards um for prepubertal and pubertal um sizes. Usually a bone age X ray is um two years advanced and true central precocious puberty. Um But we also see a lot of bone age advancement due to obesity so that keep that in mind. Um when to do a brain, MRI is always um a big question. Um Boys, um all boys should have a brain MRI if you have confirmed central puberty um by your um lab testing. Um because pathology is found in 40 to 75% of boys who have uh central precocious puberty or puberty before the age of nine. The most common finding is uh a hip hypothalamic camera toma. This is um these are associated with um gelastic seizures and then um germ cell tumors um are also and uh causes girls. Um It depends on the age and whether or not they have any central nervous system symptoms. Um in this recent uh review um in J ce and ma year ago, uh they broke it down um and reported that uh 25% of girls who have precocious puberty before the age of presenting before the age of six years have intracranial pathology. Whereas only 3% of girls between the ages of six and eight years were found to have intracranial um pathology. So, for girls who are between the ages of six and eight years, um it's important to at least weigh the risks of, you know, uh finding something incidental, um potentially needing sedation, um creating more anxiety for the parent or the child and the child and, or the child. Um And so at least, um there is, you know, the suggestion of not performing an MRI in girls if there's no CNS um symptoms. Um So what is the treatment? Um So, um excluding and treating any, any underlying cause. Um And then considering medical intervention to temporarily suppress pub and we do this for two reasons. One is to preserve final height uh in boys and girls and then the other is to delay the onset of menses and girls. So we generally treat um all boys uh to preserve their final height. And then for girls again, um, under, under the age of six, there's good data to support treating to um, improve final height um, between the ages of six and eight. there's uh a varied response um to puberal suppression and then there is no evidence that height will be increased. Um, if, um, treatment to suppress puberty is initiated in girls after the age of eight. Um However, it doesn't mean we don't treat some girls after the age of eight because um certainly you can delay the onset of, of menses um with treatment. Um So treatment um is uh done with um GNRH agonist. These are um we think of these um as super agonists because they flood the um LH receptor and um that's how they turn off central puberty. Um There's uh intramuscular leuprolide which comes as a one month, three month and six month preparations. And then there's the Histrelin or Crellin implant which has been FDA approved to suppress puberty for 12 months. But there's published um uh literature uh now showing that it is effective for uh up to two years um or even even longer. So we're using it um often for two years. Um This, these are the preparations that are available in the US. Um So, Lupper Light or Lupron depo, Lupron has been available since 1993 and the, the one month formulation um in 2007, that's when Hyster became available. Um In 2011, the three month loop uh loop ride became available in 2017. Uh The six month I am um uh preparation trip or try to lin uh became available. And then in 2020 this um fal V or the six month subcutaneous uh lro light acetate was approved. So um this is just from that article, um kind of how to approach girls with uh breast development between the ages of six and eight years. And kind of the some of the challenges um we know that the age of c Larky has decreased over time, but the age of monarchy um hasn't decreased as much. And so it seems like there's a slower tempo of puberty um among girls who have early breast development. Um and then um there are these additional considerations um which we, which we have gone through, you know, needing um a baseline LH on an ultra sensitive assay. Um The risk of doing an MRI since um there's, you know, uh little um pathology and in girls between the ages of six and eight, not improving height in girls uh over the age of eight. So, yeah, a lot of things to consider when um talking to families about puberal um evaluation and treatment, although it is um the treatments uh are are safe and the data is reassuring um in terms of bone health and fertility uh and things like that. Um So, um these are just some of the challenges. Um um and I, I think you all know this, that, that you're seeing more girls with breast development um between ages six and eight treatment um doesn't impact um height, uh always impact height at this age. Um um We're, we're getting more referrals for early breast development um since the COVID-19 pandemic. And so this brings up questions about sedentary lifestyle, increased screen time, psych, uh psychological stress. Um And then um it's important to, to also recognize that environmental factors um that are driven by socio-economic disparities may serve as confounders. And there is some risk um of missing pathology if you sort of assign uh race based guidelines in central precocious puberty. So that's why it's important to thoroughly, you know, evaluate each individual patient. Um and their personal risk factors find symptoms um independent of their BM I or their race. Ok. So, all right. So now that we've talked about early puberty, um we'll go the other direction and talk about delayed puberty. So, um for girls, uh delayed puberty is uh the lack of breast buds um uh by the age of 13 or the absence of monarchy by age 15 or three years after the onset of um 10 or two breast development. And for boys, it's the absence of testicular enlargement. By the age of 14, we see a lot more delayed puberty in males than we do in females. And there's often a history, a family history of late bloomers. So either um dad uh continued to grow after high school, um or mom had um uh late monarchy and then um usually the final height of late bloomers is uh falls within their genetic potential, but it can be on the, on the low side of the normal, normal range. OK. So this is just a typical growth curve of a boy who, who uh was kind of growing along, um pretty, pretty normally and then fell off his growth curve. And, and that's um uh for two, that's two reasons. Usually one is that um typically when other boys are um have going into their growth spurt, late bloomers, um not only are they not in their growth spurt, but they also at the same time have what we refer to as a pre pubertal slowdown. So they really kind of fall off the curve. Um And this is when usually, often we end up seeing them and then as they kind of um go into puberty, they have this delayed type of growth spurt and then they end up kind of in the lower um lower range of their genetic um potential. Um So what causes delayed puberty? So, um in girls, um it can be constitutional delay of girls in puberty, although that's less common than in boys. Um It can be um either um when you look at your labs, you're looking usually either at hypogonadotropic hypogonadism, meaning that you have low um gonadotropins. LH and FSH, this can be due to uh chronic illness, like cystic fibrosis, celiac disease, uh um inflammatory bowel disease, uh rheumatologic conditions. Um It can be psychosocial uh uh anorexia, excessive exercise, athletic triad, that type of thing. Um If they have anosmia, then you have to consider um Coleman syndrome. Um And then for hypergonadotropic hy hypogonadism, meaning that your LH and FSH levels are elevated. This is what we see in Turner Syndrome or in primary ovarian failure, which can be autoimmune or um idiopathic. Um for boys, um constitutional delay of growth in puberty is much more common and there's generally a family history. Um and again, um you, you can have hypogonadotropic uh hypogonadism with low lhfsh and low FSH. Uh again, chronic illness. Um I think I included sickle cell disease here. Um CF Celiac um boys can have anorexia or or over exercising um common syndrome, um brain tumor idiopathic. Um And then again, for um if you have elevated LH and FSH and low testosterone, this is what you see in primary testicular failure um and in Klinefelter Syndrome. So, the evaluation um after you've done your history and your physical exam um would be to evaluate for, you know, chronic disease. So, CBC metabolic panel, a sed rate, thyroid function, um usually growth factors um because usually they're presenting um with poor growth in addition to delayed puberty, um a karyotype. Um and then looking at a morning LHFSH testosterone or estradiol depending on if it's a boy or a girl. Uh again, on an ultra sensitive essay, um considering a celiac screen a bone age. Um thinking about a pelvic ultrasound in a girl. Um and then looking at um uh markers for um um testicular and ovarian function inhib and B and A MH. And then, um um I don't, did I put it? And then did they put MRI on there? I can't see on my screen. Um It would be a bone, yeah, bone agent. And then um uh MRI depending on your, on your findings, treatment of delayed puberty. Um So we um usually refer to this as a jumpstart. Um And this is again, much more common uh for boys and girls, but generally, it's a short course of intramuscular testosterone about tw about 50 mg. Um uh every month for 3 to 6 months, you should see an increase in testicular volume to about 6 to 8 MLS. Um which um indicates some endogenous production of LH. Um Once you complete your course, your short course of testosterone, you wanna wait several months and then repeat the morning LHFH and testosterone and they should be in um pubertal levels. If they're not, then you have to consider that it's um permanent um hypogonadotropic hypogonadism. And you can't necessarily know that when you um embark upon um this pubertal jumpstart for girls, you would uh consider treating with low dose estradiol for um 3 to 6 months and it can be either oral um or um transdermal with these um uh patches. And then again, um you stop the treatment, wait several months to wash out and then repeat, uh repeat the labs. Um So who should be referred? Well, certainly not, um not everybody um needs to be referred and, and not everybody even needs uh you know, a big evaluation. Um But I think at least considering and thinking about um you know, girls who are showing signs of puberty before the age of eight, or if they're progressing rapidly through puberty, um if they have monarchy before the age of 9.5, if they have any signs of virilization such as Chloro megaly, um then um those would be good um reasons to refer. Um Boys um again, uh are just uh we see early puberty in boys less often than in girls. So I think it's more important uh to refer boys who are showing early puberty. Um So if um you know, they're showing um pubic hair with um with small testes, you have to worry about um you know, an adrenal process or nonclassic cah. Um If they're showing testicular enlargement, you really have to worry about um uh CNS pathology. And uh if they're progressing rapidly through puberty, you have to worry um about pathology if they're crossing. Um percentiles early. Um if their bone age is significantly advanced. Um And if they have a morning 17 HYDROXYprogesterone that suggests ch and then for delayed puberty again, um girls who haven't started puberty by 13, haven't had monarchy by 15 or um Menzies within three years of starting um puberty. And then boys who don't have testicular enlargement by 14 or puberty that starts and doesn't progress. So, um typically when we see boys, um, adolescent boys with Kleinfelter Syndrome, they, you know, they, they, they do start puberty, they just, you know, their testes uh, remain kind of in the 10 or um, two range. Um, so, uh, if, you know, puberty begins but doesn't progress, that would be a reason to, uh, consider Kleinfelter Syndrome or other pathology. Um, and yeah, that's it.
