Klinefelter Syndrome

Explained by the Experts + Podcast

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Author and Contributing Experts to this Guide include:

Brenna Bentley Director, Patient Education at YourDNA.com LinkedIn

Klinefelter syndrome

Klinefelter syndrome was first identified in the 1940s at Johns Hopkins in Baltimore by endocrinologist Dr. Harry Klinefelter. This condition is now the most common chromosomal abnormality affecting newborn males.

What is Klinefelter Syndrome?

Klinefelter syndrome occurs in 500 to 600 cases, but because signs and symptoms tend to be mild, many people who have it remain undiagnosed.

To better understand what Klinefelter syndrome is, it’s best to start with a quick overview of chromosomes and how they function in the body.

Every person is born with 23 pairs of chromosomes in every cell (46 chromosomes total). Half of these come from the mother and half from the father.

Each chromosome is comprised of tightly wound DNA. DNA holds the specific instructions that make each individual unique. For example, DNA determines our eye and skin color, height, the level of risks for certain medical conditions, and thousands of other attributes.

In lay terms, think of DNA as a novel and chromosomes as the different chapters inside of that book.

The first 22 pairs are called autosomes and look the same in both males and females. The 23rd pair is the X and Y sex chromosomes that determine male and female biological sex, and most notably, the development of reproductive organs.

Typically, women have two X sex chromosomes, and men have an X and a Y sex chromosome.

But Klinefelter syndrome is a genetic condition in which males are born with one or more extra X chromosomes.

Their sex chromosomes could be XXY, XXXY, XXXXY, or something similar. The number of X chromosomes varies from case to case.

All individuals with Klinefelter Syndrome have a Y chromosome. By definition, this means all people with this condition are males.

In about 10% of cases, not all cells have an extra X chromosome. This is known as mosaic Klinefelter Syndrome. Individuals with this form of Klinefelter Syndrome tend to have milder features.

Klinefelter syndrome is also referred to as XXY syndrome or 47, XXY.

People with Klinefelter syndrome are occasionally referred to as X chromatin positive males.

Signs & Symptoms of Klinefelter Syndrome

The signs and symptoms of Klinefelter syndrome vary from person to person. The severity depends on how many X chromosomes are present. Those with more X chromosomes tend to experience more symptoms.

In many cases, signs and symptoms can be mild early in life, and that means Klinefelter syndrome is often undiagnosed until puberty or adulthood.

Babies often do not show any outward signs of Klinefelter syndrome. Others may be born with small testicles (hypogonadism), a small penis (micropenis), undescended testicles, or a small opening on the underside of the penis.

The most common symptom associated with this condition is infertility, occurring in 90% of cases. But this is often not diagnosed until reproduction becomes an issue later in life.

As babies grow into childhood, other symptoms may start to appear.

Muscles can be underdeveloped, resulting in delayed motor development. That can impact how and when a young child learns to sit up or start walking.

Delayed motor development can continue into the school years when a child might suffer from delays in speech and language development or reading problems. Forearm bones may not develop correctly, making it challenging to extend forearms completely.

Children with this condition tend to be taller than average with longer legs, have more fat around their stomach, and could also have a curved pinky finger or flat feet.

Symptoms can become more pronounced when a boy reaches puberty, low levels of testosterone can continue to produce symptoms noted above as well as:

  • Elevated gonadotropin levels
  • Azoospermia
  • Weaker bones
  • Narrower shoulders and broader hips
  • Increase in breast tissue (gynecomastia)
  • Less facial and body hair
  • Metabolic syndrome
  • Congenital malformations
  • Hypothyroidism

Mental health can also be an issue. Some people with Klinefelter syndrome develop anxiety and depression. They may also have difficulty maintaining attention or executing ordinary social skills.

As boys get older, they may also have a low or decreased sex drive.

According to Dr. Adrian Dobs at Johns Hopkins, “…fertility is diminished in men who have Klinefelter syndrome because of what's called a thickening of the tubules, the seminiferous tubules within the testicles. This causes the death of those cells so that the sperm is not made.

“In someone who's gone through puberty already, there is no sperm in the ejaculate. There might be very, very early on when the boy is like 12 or 13, but generally, after that first cycle of spermatogenesis that occurs, there's no more sperm in the ejaculate.”

At Johns Hopkins and several other medical centers around the world, if there is some sperm in the testes, it can be extracted through a procedure called microdissection.

“With this surgical procedure, it's possible to sort of cut into the testes and see whether or not there's any sperm that is there. The statement that all men with Klinefelter syndrome have infertility is not true, and there are men who are able to get sperm extracted from their testicles,” added Dobs.

Although infertility is due to a low sperm count or a complete lack of sperm is common, with the help of assisted reproductive therapy, some individuals with Klinefelter Syndrome can father children.

Causes of Klinefelter Syndrome

Klinefelter syndrome is caused by the random presence of extra X chromosomes in a male’s cells. Disrupted development can occur due to extra genetic information.

When there is an extra chromosome, that means that there is extra information in the cells. You're only supposed to have one sex chromosome in your egg and your sperm, but if they get stuck together, you might have an extra copy, so that when an egg and a sperm combine, instead of having two sex chromosomes, you might have three.

Individuals with Klinefelter syndrome have two X chromosomes and one Y chromosome.

Although genetic, Klinefelter syndrome is neither a dominant or recessive condition because it is not inherited.

Scientists and researchers speculate that this abnormality takes place randomly during conception, and the error takes place about half the time either due to the mother's egg or the father’s sperm.

Risk Factors for Klinefelter Syndrome

The biggest risk factor for Klinefelter syndrome is being male. Otherwise, it affects all racial and ethnic groups equally at a rate of about one in every 500 to 600 male children.

Some estimates place the frequency of Klinefelter syndrome with XXY at 150 in every 100,000 males, but other estimates indicate that cases could be as many as 1 in every 500 men.

Where three or more X chromosomes are present, it is estimated that the condition affects just 1 in 50,000 newborn males.

Another possible risk factor is that when women get older, their chromosomes tend to stick together more frequently. Technically, parents over 35 are at more risk, but because younger women have babies more frequently, in raw numbers, Klinefelter syndrome is often seen more among boys of younger mothers.

"This failure to separate is known as disassociation of the chromosomes. When separation is sluggish, there is a little extra X. Sometimes, this little extra X comes with the mother, and sometimes it comes with the father, but the child, the male child, is XY with this little extra X.

“In boys, because of this little extra X, there is a problem with the development of the testes. Although at birth they are completely masculine in their appearance, it turns out that when it comes to the time of puberty, there is a problem with the full development of the testes, so that these boys have a problem with fertility, and they have a problem with the level of testosterone that's being made in the testes,” said Dr. Dobs.

When a male with XXY uses infertility treatments to conceive, their child is at a higher risk of having the condition as well.

Can Klinefelter Syndrome be Prevented?

No. It is not inherited and is the result of a random chromosomal abnormality. At this point, there is no known way to prevent Klinefelter syndrome.

Can Klinefelter Syndrome Lead to Other Conditions?

Klinefelter syndrome can lead to several conditions, which is why an evaluation as early as possible is crucial.

There is a slight increase in learning disabilities among those boys with Klinefelter syndrome. Early diagnosis can lead to additional intervention and help in school and could have quality-of-life implications for the rest of the boy's life.

Men with Klinefelter syndrome need to be monitored every couple of years as well, even if no apparent outward symptoms exist. Lower levels of testosterone can put men at an increased risk for osteoporosis.

It's vital to do bone density tests when Klinefelter syndrome has been diagnosed.

Generally, bone density maximizes in men in their late-20s, and after that, the bone density begins to fall. If a man with Klinefelter syndrome has not had sufficient testosterone levels during his teens and his 20s, then he may never reach his maximum bone density.

That puts him at risk for the development of osteoporosis as he ages, necessitating the need for medical care throughout the man's lifetime.

Low bone density also leads to a higher incidence of bone fractures by as much as 40 fold.

Despite low or no testosterone due to Klinefelter syndrome, men can still have babies either on their own or using reproductive therapy and in-vitro fertilization.

Another complication that can result is metabolic syndrome, which affects about half of all people with Klinefelter syndrome. This is a group of different conditions such as diabetes, high blood pressure, increased belly fat, and increased cholesterol and triglycerides.

Other common secondary conditions may include autoimmune disorders such as rheumatoid arthritis, systemic lupus, and Sjogren Syndrome.

Others may be more susceptible to mitral valve prolapse, varicose veins, breast cancer, and lung disease.

Individuals with Klinefelter Syndrome tend to be shy in social interactions and introverted. As many as a quarter of all people with Klinefelter syndrome are also diagnosed with a psychiatric disturbance.

Diagnosis of Klinefelter Syndrome

When signs and symptoms are not present, the diagnosis of Klinefelter syndrome can be difficult. About 75% of all cases are never diagnosed at all, according to some estimates.

Diagnosing Klinefelter syndrome through prenatal testing is rare.

In some cases, a prenatal genetic screening test called cell-free DNA (CF-DNA) is offered to women who are 35-years or older and, therefore, in a higher risk category. The test examines DNA coming from the placenta that's floating in a mother's bloodstream.

If the screening is positive, then an actual diagnosis can take place through chorionic villus sampling (CVS) or amniocentesis, which are also often done for other reasons.

Genetic tests can also diagnose Klinefelter syndrome. When the condition is suspected, a small blood sample is drawn and sent to a lab for chromosome analysis.

From this, a karyotype will be created. A doctor will look for the aneuploidy to see if there are too many or too few chromosomes.

Another test is fluorescence in situ hybridization (FISH analysis). This is performed by placing a glowing tag on the chromosomes so that they can count the ones that glow.

Sometimes a microarray is performed. It looks at the chromosomes more closely than a FISH and a karyotype analysis, to see if there are extra or missing pieces, including an entire chromosome.

Some people get an Italian screen, an Ashkenazi Jewish screen, or other prenatal genetic tests to see whether or not someone has a genetic mutation or some genetic reason to have a child who has something affected.

Hormone tests may also be employed to measure hormone levels, including testosterone, which is a trademark symptom of Klinefelter syndrome.

If the condition is not diagnosed early in life, then it may be diagnosed during puberty when low testosterone levels may be suspected.

A diagnosis may not occur until adulthood when a man attempts to become a father and has issues with infertility.

Treatment Options for Klinefelter Syndrome

Treatment for Klinefelter syndrome can range from none at all in mild cases, to a full-blown interdisciplinary approach throughout a patient's lifetime.

Specialists such as endocrinologists, urologists, and infertility specialists may need to provide treatments above and beyond those provided by primary care general practitioners. Depending on the nature of the symptoms, occupational, speech, or physical therapists or psychologists may also be a part of the treatment team.

Testosterone replacement therapy can assist with fertility issues and may help with muscle appearance, bone strength, penis growth, and increased strength and providing a psychological boost for affected individuals. Testosterone replacement therapy delivered by injection, patch, pill, or topical cream and should be started when puberty first begins so that healthy development can take place.

Endocrinologists are often actively involved early on to assist with learning disabilities, hormonal treatments, and providing referrals to other medical professionals. Endocrinologists are also consulted to determine the best time to start testosterone therapy after the onset of puberty.

Klinefelter syndrome treatment costs can be quite expensive, depending on what is required. The need to repeat treatments or when surgery is required (such as to remove excess breast tissue) can sometimes place a financial burden on affected individuals.

Men with fertility issues can employ assisted reproductive technology (ART) to help produce more sperm.

That may include testicular sperm extraction with intracytoplasmic sperm injection, which involves removing sperm from the testes and inserting one sperm into an egg.

Can Klinefelter syndrome be cured?

Klinefelter is a rare disease, and while there have been numerous advancements in medical genetics, there is currently no cure for Klinefelter syndrome.

The Prognosis for Klinefelter Syndrome

Because it is a rare disease, life expectancy studies of Klinefelter syndrome are limited. That makes a discussion about the prognosis of someone with Klinefelter syndrome problematic.

According to Dr. Dobs, “In the untreated state, men with Klinefelter's have a slightly decreased age of death… In the treated state, most of the data would say that there's no difference in the length and the longevity of men who have Klinefelter syndrome versus those that do not have Klinefelter syndrome.”

Lowered life expectancy usually comes from complications associated with related conditions, including an increased rate of some cancers, aortic valve disease, respiratory diseases, cerebrovascular disease, and others.

What to do Next: Living with Klinefelter Syndrome

Being aware that you or a loved one has Klinefelter syndrome means you can make adjustments in your lifestyle to minimize impacts. The earlier the adjustments, the better.

For example, consuming alcohol and smoking can damage the testes, and that can result in lower testosterone levels. This is also true for people who are overweight.

Data suggests that there is also a slightly elevated risk for diabetes in this population. Monitoring and testing for diabetes and cholesterol levels can require adjustments to a person’s lifestyle to help them maintain a healthy weight and diet.

Some Klinefelter syndrome males may be able to qualify for programs like the early intervention program for infants and toddlers with disabilities. Early diagnosis and treatment can have a big impact on more traditional education and social skills as a child grows into adulthood.

The amount of information regarding Klinefelter syndrome is substantial and can help in educating someone who is trying to understand the implications of the condition better.

While there are some cases of boys and men who will suffer from complications, many others enjoy normal intellect and lead happy and productive lives with normal sexual and reproductive functions.

For parents seeking Klinefelter syndrome support, an excellent place to start is The American Association for Klinefelter Syndrome Information and Support (AAKSIS).

You might also find value investigating the assistance provided by AXYS, which is a consortium of several support groups that help parents learn, accept and find emotional support after discovering they or a family member are affected by an X and Y variation.

Finally, check with your primary care physician or an endocrinologist for support referrals near you.

Everything to know about Klinefelter Syndrome, from the experts

Hear from the experts in our conversations on a rare genetic disease: Klinefelter Syndrome. We cover Klinefelter Syndrome diagnosis, new treatment options, and how to connect with the Klinefelter community.

More resources and information for you: raredisease.com/ks

Transcript

Nate: You're listening to The Rare Disease Connection a production of Aspect Health and raredisease.com. There are roughly 7 000 rare diseases, and estimates are that a rare disease affects nearly one in 10 Americans and hundreds of millions of people worldwide. When you hear numbers like that, it's clear that rare diseases aren't so rare, and it's impossible to know how many rare diseases go undiagnosed. If you or someone you love is affected by a rare disease, you likely have more questions than answers, and that's why we're here.

Nate: Rare Disease Connection and our additional resources on raredisease.com and yourdna.com bring together the people whose expertise can explain what you're facing from diagnosis, to prognosis, to treatment options. All the way to questions like, who do I talk to, and where are the people who've been through this before? You'll find those answers here from doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families are all within your reach. We're here to connect you. This is Rare Disease Connection.

Nate: Hey everybody, this is Nate, cohost of Rare Disease Connection and a co-founder of Aspect Health. Once again, I'm excited to bring you some recent conversations I've had with experts from around the world about a very specific rare genetic disease, Klinefelter syndrome. Before you listen, we know that hearing from these experts is only the beginning for you. That's why we've taken the information here in this episode and we've added additional resources, other explanations, links for you and references, all in a downloadable guide on Klinefelter syndrome. You can get over to raredisease.com/ks and you'll get a free copy of that guide. Once again, go to raredisease.com/ks after you listen and get all those additional resources from us. Please do so, head over there, because there's so much more that we've pulled together to help you on your journey in understanding this disease. It will certainly help support you and your ongoing plan of action.

Nate: The experts are here, so let's talk about Klinefelter syndrome. Our first conversation is with Brenna Bentley. She is currently in clinic completing her masters in genetic counseling at the University of Alabama, Birmingham. Let's let her introduce herself and then we'll walk through defining this disease, how it's diagnosed and who it affects.

Brenna Bentley: Like you said, I'm a genetic counseling student, currently at the University of Alabama, Birmingham. I'm in my second and final year and will be graduating on May 1st. I'm about to move up to Danville, Pennsylvania to my last two rotations up there. And so far I've had a chance to rotate almost through all different specialties, and I've particularly enjoyed prenatal and pediatrics, so I am looking to see where that takes me in the future. And right now I'm still open.

Brenna Bentley: Sort of quick refresher, each person is made up of trillions and trillions of cells, and in each of these cells are a of instructions, that's called DNA, and that helps tell us what to do. It can do everything from determining our eye color, our skin color, to even our height and certain risks to have certain different conditions. However, the DNA is quite large, and so to be able to fit in all of those cells, it has to get organized some way. And so it's organized into different sections called chromosomes. And you can sort of think of DNA as a novel and chromosomes as the different chapters inside of that book.

Brenna Bentley: Humans have 23 pairs of chromosomes, half of them come from our mom, half come from our dad, and the last pair of chromosomes are special, they determine our sex. Females have two X chromosomes and males have an X and a Y.

Nate: Brenna, speaking from your experience as a GC, what immediately comes to mind when you hear the term Klinefelter syndrome?

Brenna Bentley: Initially when I think of Klinefelter syndrome, I think of a chromosome condition that's more common than a lot of people realize. In fact, it occurs in every one to 500 to 600 newborn males, and it's actually the most common sex chromosome condition. But because the features of this condition tend to be really mild, there's a lot of individuals who don't know that they have this condition and it actually goes undiagnosed quite frequently.

Nate: Let's talk a little bit about the science, I guess, behind the causes of this disease. What specific genetic mutation causes Klinefelter syndrome?

Brenna Bentley: Sure, so sort of what I was alluding to in my chromosome introduction, this one will be focusing on that last pair of chromosomes, so sex chromosomes. And so typically, like I was saying, females have two X chromosomes and males have an X and a Y, and there's a special cell division that makes our eggs and our sperm, which end up combining. However, sometimes chromosomes in those cells get stuck. You're only supposed to have one sex chromosome in your egg are in your sperm, but if they get stuck together, you might have an extra copy, so that when an egg and a sperm combines, instead of having two sex chromosomes, you might have three. Individuals with Klinefelter syndrome actually have two X chromosomes and one Y chromosome.

Nate: And if we were to look at pictures of individuals with Klinefelter syndrome, what might we see, what characteristics?

Brenna Bentley: They're very mild and tend to look just like anybody else, which I think is a big reason why this often goes undiagnosed. Some things that you can see is these individuals might be a little bit taller than what you would expect based on their parental height, and they might have a few differences, like differences in the bones in their forearm, which could make it difficult for them to fully extend their elbows. They might also have some flat feet or a pinky finger that's a little bit curved, but overall it's important to know that some people with Klinefelter syndrome might not have any of these signs or symptoms, or they might just have some of them.

Nate: Getting back to the chromosome itself, you said an extra X chromosome, what actually happens if you have extra X chromosome in this case?

Brenna Bentley: Yeah, so in this particular case, if you're born with an extra X chromosome, and you have a Y chromosome, you will be born a male and you'll have Klinefelter syndrome along with these potential different signs and symptoms that we were talking about above. If you have an extra X chromosome, but also have two other X chromosomes, then you'll actually have a condition that's called triple X syndrome, which looks different than Klinefelter syndrome.

Nate: Who is actually most likely to get Klinefelter syndrome, just to kind of belabor the point a bit, and what are the chances of having a child with this condition?

Brenna Bentley: Klinefelter syndrome affects all racial and ethnic groups equally. It's a condition that occurs by chance, and it's not one that's caused by a parent passing this condition down to their child. It actually occurs, like I said, in about one to 500 and 600 newborn males, which is roughly 0.2%, so not even 1%. And that means that your chance to not have a child with Klinefelter syndrome is much, much greater than your chance to have a child with this syndrome. That being said, as women get older, their chromosomes tend to stick together a little bit more frequently, sort of in that special process I was talking about earlier that actually makes the egg and the sperm. Therefore, as women get older, their risk to have a child with a condition where they might have that extra or missing chromosome, like Klinefelter syndrome, increases. But you also have to think about, it tends to be younger women that have babies more frequently, and so it's more common to see actually a baby with Klinefelter syndrome born to a younger woman even if the risk is increasing with age.

Nate: What are other common [centrums 00:07:39] we might see in an individual who has Klinefelter syndrome?

Brenna Bentley: The condition's really mild, like I was mentioning, and it's predicted that actually 75% of men with this condition are never diagnosed. Thinking about it through different points in their life of what sort of symptoms might arise, in childhood you might see muscles that are a little bit underdeveloped, which might delay their motor development, such as sitting up or walking on time. You might also see differences in their genitalia such as testes that didn't descend or a micropenis.

Brenna Bentley: With children as they start to develop school, the other things like learning disabilities might become more evident, as they might need a little bit more assistance, specifically with reading and language skills. Some of the more common symptoms that might arise a little bit later, such as in adolescents or when they go to have a family of their own, can be some issues with infertility. That being said, with Klinefelter syndrome, there have been successes though with using assisted reproductive therapy, like in vitro fertilization, so that these individuals could go on to have children of their own.

Brenna Bentley: And lastly, there is an increased risk for these individuals to have something called metabolic syndrome, which is essentially a group of different symptoms such as diabetes, high blood pressure and increased cholesterol, so it's important that if people have this condition, that they're aware of those risks and that their doctors know as well so that they can be monitoring those things. But just like with the physical symptoms, an individual with Klinefelter syndrome might not have all of these or any of these particular signs and symptoms, and that there are therapies that can help with the different areas of this condition.

Nate: Let's talk a little bit about the actual diagnosis of Klinefelter syndrome, kind of when and how this is figured out for those that do have it, in the percentage that do end up being diagnosed. At what age is Klinefelter syndrome usually diagnosed, when it is diagnosed?

Brenna Bentley: There's three main points in life that an individual would typically be diagnosed with Klinefelter syndrome. And the first is actually prenatally, so before they're even born. A prenatal genetic screening test called cell-free DNA is often offered to women who have advanced maternal age, or who might be at high risk due to some previous prenatal screening. This test looks at pieces of DNA coming from the placenta that's actually floating in mom's bloodstream. And oftentimes the placental DNA is the same as baby's DNA, but it's not always the same, which is why this is considered to be a screening test and not one that's diagnostic, but it does look at the sex chromosomes, and since Klinefelter syndrome involves the sex chromosomes, it could come back stating if the baby might be at an increased risk for this condition. And if it comes back with an increased risk, then there could have the option of a diagnostic procedure like an amniocentesis, which would look at fetal cells that are actually in the amniotic fluid that baby's floating in, and that would be considered diagnostic because it's actually looking at cells from baby and not from the placenta. That's one point where a lot of individuals end up actually receiving a diagnosis.

Brenna Bentley: And some other common time points are around puberty, especially since, as I mentioned, they sometimes have some difficulty with testosterone, which comes into play during puberty very significantly. If there's issues, they might receive a diagnosis then. Or then, when they go to have their own family and might be experiencing issues with infertility.

Nate: As far as other genetic tests, we all know that there's a lot of different tests always coming to market, for lack of a better term. If you look at the current landscape of genetic tests for Klinefelter syndrome, what else is out there or what else might we address?

Brenna Bentley: In order to actually diagnose Klinefelter syndrome, they're going to have to take a close look at the individuals chromosomes. And so there's a couple of different ways they can do that. First they're going to need a sample. Sort of as I mentioned there, you can take from amniotic fluid, where when baby's prenatally, or after birth, they can also use blood. And there's other specimens like tissue biopsies that can actually be used as well. However, amniotic fluid and blood tend to be the most common that are used.

Brenna Bentley: And then there's a few different tests that they can use to actually diagnose this. They use tests such as a FISH analysis, which stands for fluorescence in situ hybridization, which is essentially where they have a little glowing tag that they put on the chromosomes and they're able to count the ones that glow. They could make a tag for the X and Y chromosomes and be able to see how many that there are. There's also a karyotype, which is essentially taking a picture of an individual set of chromosomes, and they could again count their sex chromosomes. And a microarray, which looks at the chromosomes more closely than a FISH and a karyotype analysis, and they could see if there's extra or missing pieces, including an entire chromosome.

Nate: And so previously you mentioned some of the cell-free DNA tests being prenatal options for mothers, specifically I guess, to address that again, are there any prenatal tests for Klinefelter syndrome?

Brenna Bentley: There's not necessarily a test that you come in and say, "I want to know if my baby has Klinefelter immediately." Unless that's something that you're worried for, and you might do that amniocentesis or chorionic villus sampling. Most of the time women learn about this because they did undergo that screening test that I mentioned earlier, that cell-free DNA that came back with an increased risk. And so, if it has that increased risk, then depending on where the mom is in her gestation, we would talk about which diagnostic tests are available to her.

Nate: Well, jumping ahead to something potentially more interesting or exciting, is there a cure coming for Klinefelter syndrome, or what's the landscape for that right now?

Brenna Bentley: Unfortunately, at this point in time, there's not a cure for Klinefelter syndrome, and there's not really one on the horizon. Conditions that are involving an entire chromosome, that's a lot of genetic information. And so scientists are still, I would imagine, working on that for cures and whatnot. But at this point in time, things are focused more on therapies and treatments that can be used to help these individuals.

Brenna Bentley: Some things like testosterone treatment can really help with some of the muscle appearance, increasing their strength and improving self-esteem for these individuals. But there's also resources such as speech, occupational and physical therapy, to again help with the muscle development and any learning disabilities.

Nate: Given that, and I guess in your professional opinion, what is the best advice from you, for someone who is either diagnosed with a Klinefelter's or has a child or a loved one who is diagnosed?

Brenna Bentley: First, I would say that it's no-one's fault that the child has Klinefelter syndrome. There's nothing that someone did or did not do to cause this. I would want them to know that they're not alone. There's a lot of individuals living with Klinefelter syndrome and there are wonderful support groups and resources available for this population. For example, there's a group called Living with XXY, which is the genetic sex chromosome makeup of individuals with Klinefelter syndrome, and they focus on increasing awareness about the traits and the successes of individuals with this syndrome. Additionally, there's the American Association for Klinefelter's Information and Support, and it provides wonderful support and education resources. And finally, as I mentioned, Klinefelter syndrome tends to be a lot more mild than other chromosome conditions, and these individuals can, and often do, go on to live really healthy and happy lives.

Nate: Thanks to Brenna for her insights. Whether you've interacted with a genetic counselor yet or not, they do play an invaluable role in the journey of anyone diagnosed with a rare genetic disease. Our next conversation is with Dr. Adrian Dobs. Dr. Dobs is the lead physician in evaluating men for the medical complications of Klinefelter syndrome. She's out of Johns Hopkins in Baltimore, which is one of the foremost clinics providing treatment for this disease.

Dr. Adrian Dobs: My name is Dr. Adrian Dobs, and I'm professor of medicine and endocrinology here at Johns Hopkins University School of Medicine. My specialty within endocrinology is on sex hormones, which means I take care of patients who have, men who are maybe too low testosterone levels, and women that have too much testosterone levels. And Klinefelter syndrome is one of the many medical problems that I'm involved in the care of these patients. It turns out that Harry Klinefelter, who the disease is named after, the condition, was from Baltimore and was at Hopkins, so we have a very large population here at Johns Hopkins. And in fact, we have what's called a center, the Johns Hopkins Center for Klinefelter Syndrome. We have a whole team of people that have a multidisciplinary approach to this condition.

Nate: And speaking from your experience, as a professional, what immediately comes to mind when you hear those words Klinefelter syndrome?

Dr. Adrian Dobs: Klinefelter syndrome, first of all, the name is quite awkward, and it comes from a time when many medical problems were named after the physician at first described the condition. We try not to do that much anymore because there was just so many names that it was very hard for any poor medical student to remember. But this is something that seems to have stuck, because the more medical term is just as long and confusing.

Dr. Adrian Dobs: One of the things that I think is important to emphasize, is that this is a medical problem that is underdiagnosed. It's really not that rare. It's probably in one in 750 live births, which is not a very rare condition, but it oftentimes goes undiagnosed throughout life, and certainly goes underdiagnosed where it's not picked up until later on in life. Particularly, the most common time it's picked up is when a man might be in his late-20s or early-30s and he and his wife are found to be infertile, and it's at that time that it's often made. But it's really a shame because there are some approaches to this condition that's important to make the diagnosis very early on in life.

Dr. Adrian Dobs: There are more times now where we're seeing children that are picked up on prenatal testing. I think that will definitely change the landscape. But as a physician who takes care of adults, I find that it's often underdiagnosed and I don't see men until they're quite later in life.

Nate: And so who does it most typically affect, if there is a bucket of people, or gender, or whoever that this disease might show up in more than others?

Dr. Adrian Dobs: Well, it obviously is a condition that's only in men, but it does not go for any particular ethnic group. There is some association with older parents, because the genetics of this is that there's a problem with what they call disassociation of the chromosomes. You know that a female is an XX and a male is an XY. Well, sometimes there's what I call a sluggishness to that perfect separation. And what happens is that there is a little extra X. Sometimes this little extra X comes with the mom and sometimes it comes with the father, but the child, the male child, is XY with this little extra X.

Dr. Adrian Dobs: Now, because there's a Y, the boy is a boy. But because of this little extra X, there is a problem with the development of the testes in these young boys. It turns out that although at birth they are completely masculine in their appearance, it turns out that when it comes to the time of puberty, there is a problem with the full development of the testes, so that these boys have a problem with fertility, and they have a problem with the level of testosterone that's being made in the testes.

Nate: Are there any other physical characteristics that manifest with this disease?

Dr. Adrian Dobs: Right, so they look pretty distinctive, some of the men, not all, but some. And what I mean by distinctive is that many of them are tall. And the reason for this is a couple. One is that they go through a late puberty, and that means that their bones haven't fused, because what puberty does is there's a very high level of testosterone and that closes what's called the epiphysis of the bone, and that stops boys from growing, it stops girls from growing as well. Because they don't go through a full puberty, many of these boys are tall. But there's probably some other reasons as well, because it turns out even before puberty, they tend to have longer long bones. That means they have a longer leg, their legs are longer, their arm span is longer.

Dr. Adrian Dobs: Now, they also can present with this sense of, besides height, they can also have gynecomastia, which is the fancy term for some breast development. Now, it turns out that many, many boys as they go through puberty will have what's called pubertal gynecomastia, but this is much more commonly seen in teenage boys who have Klinefelter syndrome.

Dr. Adrian Dobs: Another typical finding is that because they don't go through a full puberty, you'll see that they have a delay in their beard growth, a delay in their body hair, and they classically will have small testes. In fact, that's probably the most consistent finding among men with Klinefelter syndrome, is that they have small testicular size.

Nate: We've got some diagnosis parts laid out. What about prognosis, life expectancy, and what is just the general prognosis for someone who finds out they have Klinefelter syndrome, whether it's younger or maybe later in life?

Dr. Adrian Dobs: Right, so the data is not that clear, because we don't have good, very large studies, but ... And there have been some studies done in Europe, particularly in Denmark where they have better databases of every person in their country. In the untreated state, men with Klinefelter's have a very, very slightly decreased age of death. And the reasons for this is not clear. Sometimes it's because of blood clots, because they have relatively more estrogen than testosterone. And there's some other data that there may be some slight increase in some cancers. But that's in an untreated state, and even that is quite mild.

Dr. Adrian Dobs: In the treated state, most of the data would say that there's absolutely no difference in the length and the longevity of men who have Klinefelter syndrome versus those that do not have Klinefelter syndrome. That probably is no different.

Dr. Adrian Dobs: There may be some additional problems though, and that's why it's important to evaluate this early on. And one is that there's a big concern about learning disabilities. This has been hard to document, because in reality we all have learning disabilities, we just have to learn how to deal with it. But there's a slight increase in the prevalence in young boys with Klinefelter syndrome, so that points to a reason why an early diagnosis is better. These children may need some additional help in school, and this will help them later on in life. As I say, most learning disabilities, people learn to accommodate themselves and find the best ways to learn, but it would be nice if the diagnosis was made early, and therefore kids could get some kind of early intervention to help them learn how they can succeed better at school.

Nate: You mentioned some of these, this is sometimes discovered prenatally now, but there's a lot of diagnosis that happens in late-20s, that are tied to fertility. What are the genetic testing options, or just general testing options that are out there being used currently to discover Klinefelter's at these different stages?

Dr. Adrian Dobs: There's reason that this would be really done unless there was another reason to be tested. Generally, this is not done in a vacuum. But individuals in which there's genetic testing that is done, depending on how extensive it is, this will be picked up if the baby is already, is growing and is during a pregnancy. This is not going to be picked up if one is doing a prenatal screen, and there's lots of those around now. One can get an Italian screen, an Ashkenazi Jewish screen, and these are all prenatal tests to see whether or not someone has a genetic mutation, or some genetic reason to have a child who has something affected. You wouldn't know this condition until after there's a pregnancy, because again, the genetics of this is that there is a disassociation, there's not a good separation between that X and the Y chromosome, so this happens right before, basically before conception. And so that wouldn't be picked up. But it would be picked up early on if one is doing any chromosomal testing.

Dr. Adrian Dobs: We do get calls quite frequently about, from couples around the world who say, "Oh, I was just found out that I have a baby boy with Klinefelter syndrome. What do you think? What's the prognosis? And what's going to be this life expectancy in the way of a productive life?" We're obviously very positive about that, and we certainly believe that with testosterone treatment it will, these men have very normal, normal lives. They generally do require testosterone therapy for full puberty. But with treatment, these men do quite fine.

Dr. Adrian Dobs: Of course, they don't do fine when it comes to the issue of fertility, Their fertility, it definitely is diminished in men who have Klinefelter syndrome. And this was because of what's called a thickening of the tubules, the seminiferous tubules within the testicles. And this causes a death of those cells, so that the sperm is not made. In someone who's gone through puberty already, there is no sperm in the ejaculate. There might be very, very early on, when the boy is like 12 or 13, but generally after that first cycle of spermatogenesis that occurs, there's no more sperm in the ejaculate. However, there can be some sperm in the testes. And here at Hopkins, and at several other places throughout the world, the procedure is now what's called a microdissection, a testicular extraction of sperm. With a surgical procedure, it's possible to sort of cut into the testes and see whether or not there's any sperm that is there. The statement that all men with Klinefelter syndrome have infertility is not true, and there are men who are able to get sperm extracted from their testicles.

Nate: I'm glad you talked about some of the treatment options that are available today. I'm curious, can you can tell me a little bit about the role of a physician, and the ongoing treatment and lifespan of someone with Klinefelter's? Are you the one who is, or is the physician the one, typically who's coming up with these treatment options and referring them? And then also, what's the ongoing relationship over time?

Dr. Adrian Dobs: Obviously an educated consumer, an educated patient, is your best partner here. But it does need to be in concert with a physician. This condition is, the treatment is usually given by an endocrinologist when it comes to the hormonal treatment. Once a plan is made, then oftentimes a primary cam physician could take on this role as well, with less frequent visits to an endocrinologist. Urologists can be involved with this care as well, particularly when there is a question about fertility and how best to treat fertility. There does need to be ongoing involvement with an endocrinologist. In the beginning, it may be for purposes of this learning disability and the proper referrals, that would be in a young child before puberty. After puberty, there would be a need for the endocrinologist to determine when is the best time to start testosterone therapy. And then in the 20s, the best, that would be the time where a urologist would usually get involved for purposes of fertility.

Dr. Adrian Dobs: And then really throughout the lifespan, I think the men need to be followed at some level. It could be once a year, once every few years, by a specialist, to see whether or not there is anything new that has been learned. One of the big issues that we see in older men is if they have not been treated with testosterone early on, this is an increased risk for osteoporosis. Osteoporosis is thinning of the bones, and this is, we think of it commonly for women as they get older, but it definitely occurs in men just as well, particularly a man who has had insufficient testosterone levels throughout most of his life. We always measure bone density in this population and follow this as the man ages. There is a drop in bone density that occurs with just age, and then combine this with the fact that they may not have, these men, may not have fully developed their bone density. Generally, bone density maximizes at sometime in their late-20s, and after that the bone density begins to fall. If a man with Klinefelter syndrome has not had sufficient testosterone levels during his teens and his 20s, then he may never reach his maximum bone density, and therefore they would be at risk for the development of osteoporosis as he ages. We think that there is a need for medical care throughout the man's a lifespan.

Dr. Adrian Dobs: Now, I do want to mention this is multidisciplinary. I've already mentioned an endocrinologist, and a primary care doctor, and a urologist. I've already mentioned the fact that sometimes it needs to be special testing to see whether or not there's any educational or cognitive issues. And I also think that sometimes there is a need for some kind of therapy, more talk therapies. There is no actual problem, or there's no increased likelihood of a psychiatric disease, but in some men it can be difficult, so that I think that they should have access to a psychotherapist if that's what they might need.

Dr. Adrian Dobs: It can be difficult for both men and women when they realize that there's some problems with their fertility. Infertility is very common in the population, it occurs in about 15% of couples, regardless of their ethnicities, and it can be quite difficult for patients.

Nate: I did want to ask as well, this is just kind of brief, but are there any lifestyle changes that get suggested or meaningful lifestyle changes that can be made in response to a diagnosis of this disease?

Dr. Adrian Dobs: There's always ... A man wouldn't want to do anything that would make his testosterone level any worse. And there's some data on smoking that can damage, alcohol can damage the testes. Even being very overweight can also lower testosterone levels. A healthy lifestyle is a good thing no matter what is going on. There's some slight data about an increased risk of diabetes in this population. This is something that we monitor here. We monitor cholesterol levels as well. We would treat this, if it turns out that they do diabetes. Lifestyle modification to maintain a healthy lifestyle and a healthy diet and weight I think are always important.

Nate: And finally Doctor, what is your best advice for someone who is diagnosed with Klinefelter syndrome, and are there any resources or organizations that you also suggest they check out?

Dr. Adrian Dobs: There is a fair amount of education that's out there about this specific disease. I think this is an advantage because it is very specific. There's really a wonderful support group that's called themselves [AXYS 00:33:08], X-X-Y-S, I think is the abbreviation, and they are really a wonderful group, a big support group. A lot of parents are involved, a lot of individuals are involved. They have good educational materials. They sponsor meetings and programs. Education of the patient, no matter, I say this generally and certainly specifically here for men with Klinefelter syndrome, is to learn as much as you can about the condition.

Dr. Adrian Dobs: I do want to emphasize, normal intellect, normal IQs. Certainly most men will have very happy, productive lives with normal sexual function. But I think that this helps if there's an awareness that there could potentially be some medical problems and that this needs to be investigated ... This needs to be followed.

Nate: Thank you Dr. Dobs. After hearing those conversations, we all find ourselves with this small bit of information that only might leave you wondering, "Okay, what now?" So what now? Like we said at the beginning, we know that hearing from these experts is only step one. That's why we've taken all the information and created additional resources in our downloadable guide on KS. You can get your free copy of that guide, once again, by going to raredisease.com/ks. You can also download a recap of this episode and other episodes, and get key points, as well as several links and resources for you to further explore.

Nate: Finally, as always, if you need someone to speak to directly about Klinefelter syndrome or just your own personal situation currently, we are here to help. Visit raredisease.com/help and get in touch. We are standing by.

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