Pediatric Von Willebrand Disease: Practice Essentials, Pathophysiology, Epidemiology
HHMI Researchers Devise Prenatal Blood Test That Accurately Detects Down Syndrome And Two Other Serious Chromosomal Defects.
Howard Hughes Medical Institute researchers have developed a new prenatal blood test that accurately detected Down syndrome and two other serious chromosomal defects in a small study of 18 pregnant women. If confirmed in larger trials, they say, the test would offer a safer and faster alternative to invasive prenatal tests such as amniocentesis that pose a small risk of miscarriage.
Researchers have long known that a pregnant woman's blood contains small amounts of DNA from the fetus. Howard Hughes Medical Institute researcher Stephen R. Quake and colleagues at Stanford University devised an ingenious way to the scan fetal DNA present in the mother's blood to determine whether the fetus' cells contain extra chromosomes associated with several types of severe birth defects.
The test developed by Quake's team was more accurate than techniques used in previous efforts to diagnose aneuploidy by analyzing fetal DNA. Aneuploidy occurs when there are either too many or too few chromosomes in cells. Down syndrome, for example, is caused by a trisomy—three copies instead of two—of chromosome 21.
"We believe this is the first demonstration of a universal, noninvasive test for Down and other aneuploidies," said Quake, senior author of the research article, which was published online in the early edition of the Proceedings of the National Academy of Sciences (PNAS) on October 6, 2008. "We need a larger clinical study to understand a bit more about the best way to implement it, but I am highly optimistic it will be used as a diagnostic test in short order."
Amniocentesis and chorionic villus sampling (CVS), which are currently considered the "gold standard" in prenatal testing, involve sampling cells in amniotic fluid. Those cells are obtained by inserting a needle into the mother's uterus. The procedure carries up to a one percent risk of inducing a miscarriage. For that reason, routine use of these invasive diagnostic tests has largely been limited to women age 35 and older, where the age-related risk of fetal aneuploidy outweighs the risk of miscarriage. As a result, more infants with chromosomal defects are now being born to younger women. Researchers have been working for years to devise noninvasive screening tests that would be safe for that group of women.
In addition, it takes two or three weeks following the amniocentesis or CVS procedures to culture the cells and study the chromosomes. That amount of time can seem like an eternity for anxious parents waiting for the test results, Quake said.
With the new test, scientists only need to draw a small amount of blood from the woman. The blood is analyzed and the results are available within a couple of days, said Quake, who is a bioengineer at Stanford.
Quake's interest in developing new technology to diagnose aneuploidies was sparked when he read a research article published in the journal Science in 2005. That article discussed new methods of noninvasive prenatal testing that relied on measurements of DNA in fetal cells present in the mother's blood. The report said that the low prevalence of fetal cells—only about one in one million maternal cells—made it difficult to isolate enough of fetal cells to test for chromosomal abnormalities.
At the time, some researchers were trying to isolate fetal "cell-free DNA" from the mother's blood. Cell-free DNA is fragmented double-stranded DNA that is in the debris of dying fetal cells. Isolating this DNA was a good idea, Quake said, but recovering the vanishingly small amount of fetal cell-free DNA remained a challenge.
After reading the Science article, Quake thought to himself, `A lot of my work is about counting molecules; this is one problem I know how to do.' He had a brainstorm: Where other researchers were developing various ways of amplify the fetal DNA signal to distinguish it from maternal DNA, Quake proposed a bold shortcut—skipping that step entirely. After all, he observed, the point of screening was to spot extra chromosomes in the woman's blood sample. Whether the DNA being scanned was from the fetus or from the mother didn't matter. The objective, therefore, was simply to measure the amount of DNA in fragments mapped to the different chromosomes.
Conveniently, the cell-free DNA floating in the mother's blood circulation normally exists in short pieces, averaging 169 nucleotides in length. Quake proposed a "shotgun sequencing" strategy where he would use the very latest high-throughput gene sequencing technology and equally powerful computers to identify millions of unique sequence "tags" in the fetal DNA. Each of these tags was a 25 base-pair fragment of DNA. After the tags were identified, Quake's group could then map them to specific locations on the 23 pairs of chromosomes. By using this strategy, the researchers believed they could detect higher-than normal amounts of DNA belonging to the three chromosomes involved in the most common aneuploidies—chromosomes 21, 18, and 13.
In the experiments reported in PNAS, Quake and his colleagues, including first author H. Christina Fan, a graduate student in bioengineering at Stanford, used their new technique to analyze DNA in blood samples from 18 pregnant women who were undergoing invasive prenatal testing (and one man, for reference).
When the amounts of DNA corresponding to each chromosome were plotted on a graph, significant, above-normal peaks appeared when a chromosome was present in three copies instead of two. These signals enabled the scientists to correctly identify the 12 women who carried aneuploid fetuses and the six whose pregnancies were normal. Their results matched those of amniocentesis or CVS test that were done on the women.
Quake said the shotgun-sequencing system is not only safer than invasive techniques but can also make a determination at an earlier gestational age, around 12 weeks.
The earlier the couple knows the status of the pregnancy, Quake observed, the better they will be prepared for whatever decision they choose to make on the basis of the information.
Quake's group is now planning a follow-up study to evaluate the test in a larger group of patients. He estimates that the cost of the test during the next phase will be about $300, with DNA sequencing accounting for the majority of the overall cost.
Pregnant At 40: What To Expect
While 1 in 4 people in their 20s and 30s will get pregnant in any one menstrual cycle, only 1 out of every 10 people will become pregnant in any one menstrual cycle by age 40. At this age, you have a 44% chance of pregnancy within 1 year. This is because as you get older, the number of eggs in your ovaries decline. With age, you're also at a higher risk for disorders that affect your fertility.
If you get pregnant after 35 years old, experts call this an "advanced maternal age" pregnancy. But it's still possible to get pregnant and deliver a healthy baby in your 40s. Childbirth at older ages has become more common too. Since the 1990s, birth rates in people aged 40-44 have gone up. To prepare for a baby at 40, it's important to consider the risks and benefits.
By age 40, if you're healthy, you have only a 5% chance of getting pregnant per menstrual cycle.
At the same time, the likelihood of miscarriage climbs with your age. A typical 40-year-old has about a 40% chance of losing the pregnancy. That compares to less than 15% for someone in their 20s.
By the time you're over 45, the American College of Obstetricians and Gynecologists says getting pregnant naturally is "unlikely for most women."
As you age, so do your eggs. And you have fewer of them, too. You're born with all the eggs you'll ever have in your life, about 1 million. By the time you hit puberty, you may have about 300,000 left. At 37, you're down to just 25,000 -- or 2.5% of your starting count. That matters because the fewer eggs in your ovaries, the lower your odds for conception.
Even if you do get pregnant, your older eggs are more likely to have abnormal chromosomes, which may raise your chance of miscarrying your baby. Also, if you're 25-40, you are more likely to have problems like endometriosis and uterine fibroids that make it harder for you to get pregnant.
The quality of your partner's sperm also matters. As men age, their sperm tend to swim slower and begin to lose their shape. But sperm quality doesn't drop steeply until after men enter their 60s.
In people who can get pregnant, the peak reproductive years span the time between your late teens and late 20s. Your fertility will begin to go down around age 30. This process continues more quickly starting in your mid-30s. Once you reach 45, your fertility will usually be so low that a natural pregnancy is unlikely for most people.
But some people may still have a "menopause baby." This refers to a pregnancy and delivery that happens when you're in perimenopause, the transition into menopause.
The sperm-producing parent may also have a decline in fertility with age. While this isn't as predictable, it could still affect your chances of pregnancy at 40.
Other risks of pregnancy at 40 include complications that are more common at this age. Older women tend to have more health issues than younger women, such as high blood pressure.
This condition can put you at a higher risk for preeclampsia, which is when you suddenly develop high blood pressure and signs of organ damage while pregnant. If left untreated, this can lead to serious or fatal problems for you and your baby.
But later-in-life pregnancies can also affect the health of your baby, even if you don't have any health conditions. If you get pregnant at 40, you'll have a higher risk of:
A higher birth weight of your baby. One study found that the risk of macrosomia (or a higher birth weight of your baby) goes up with age.
Placenta previa. This happens when your baby's placenta either partly or completely covers your cervix, which is the exit area of your uterus. With this condition, you may bleed more while pregnant and during your delivery.
Gestational diabetes. This is when you get diabetes for the first time while you're pregnant. It causes high blood sugar that can affect your baby's health and your pregnancy.
Gestational hypertension. This is high blood pressure that develops during pregnancy. It's different from preeclampsia, which is a blood pressure complication during pregnancy. Preeclampsia is also more common in older women even without hypertension.
Miscarriage or stillbirth. You're more likely to have a miscarriage if you're older. At age 40, 27% of pregnancies end in a miscarriage compared to 16% for those 30 or younger.
C-section. If you're 40 or older, you're more likely to have a C-section delivery than a vaginal delivery.
Down syndrome. The risk of having a child with Down syndrome goes up as you age. At the age of 20, 1 in 1,480 children will be born with the condition. But at age 40, this risk goes up to 1 in 85. At age 45, your child's risk is 1 in 35. Other chromosomal abnormalities are also more common.
Need for a blood transfusion. This can help save your life in an emergency blood loss situation during pregnancy. But it comes with the risk of complications as well.
While there are more health risks with pregnancy at 40, there are also some upsides to later births. You may:
Studies have also shown that a child later in life may lower your mental decline, lengthen your life, and lead your child to have better educational results (like higher graduation rates and test scores).
To prepare to have a child, it's important to create a reproductive life plan. With this, you and your doctor can prepare for you to have children at your desired age.
If you want to get pregnant now, make sure you're as healthy as possible. Stop alcohol, marijuana, and tobacco use. Talk to your doctor about prenatal vitamins with folic acid.
Visit your doctor to chat about your diet and lifestyle, sexually transmitted infection (STI) screening, a healthy prepregnancy weight, and any other concerns before you get pregnant. Everyone should make an appointment before they try to get pregnant, but this is especially crucial if you're 40 and older.
If you don't want to get pregnant now but may want to have a baby at an older age, talk to your doctor about:
In vitro fertilization (IVF). With this method, experts combine a sperm and egg in a laboratory to grow an embryo. Your doctor can then freeze the embryo for later use.
Oocyte cryopreservation. This is when your doctor freezes your eggs. They'll take some of your eggs from your ovaries and freeze them so you can use them later in IVF.
You can still get pregnant naturally at 40, but these methods may heighten your chances of having a baby at a later age. However, many of the risks will still be present.
What Is Turner Syndrome?
Turner syndrome is a rare genetic disorder found in some women and people assigned female at birth. It can cause short stature and a range of health issues including heart defects, learning disabilities, and infertility. Sometimes, symptoms are so mild that the disorder isn't diagnosed until teen or young adult years.
Turner syndrome can cause symptoms throughout your life. Treatments and findings from ongoing research can help you manage its symptoms. About 70,000 women and people assigned female at birth in the U.S. Live with Turner syndrome.
A pediatrician should be part of your child's Turner syndrome care team. (Photo Credit: E+/Getty Images)
Turner syndrome happens when a female is missing certain genes normally on the X chromosome. (Females have two X chromosomes, while males have an X and a Y chromosome). Some people with Turner syndrome are missing a whole copy of the X chromosome. For others, just a part of the X chromosome containing a specific set of genes is missing. Almost 99% of babies with a missing X chromosome are miscarried, but about 1% of them are born with Turner syndrome.
Turner syndrome has different types depending on the way your genes are affected.
Mosaic Turner syndrome. When cell division during the early stages of fetal growth doesn't happen correctly, some cells in your body get two complete copies of the X chromosome. Other cells have only one copy.
Monosomy X. In this type, a problem with the mom's egg or dad's sperm causes an absence of the X chromosome in every cell of the body.
Inherited Turner syndrome. A baby may inherit Turner syndrome from a parent who has the condition. This type is very rare and often occurs due to an absent part of the X chromosome.
Other Turner syndrome abnormalities include:
X chromosome abnormalities. These can happen when your cells have one complete copy and one abnormal or missing copy of the X chromosome.
Y chromosome material. In a few cases, some cells get one copy of the X chromosome, while other cells get one copy of the X chromosome and some Y chromosome material. Biologically, you develop as a female. The Y chromosome material increases your risk of a type of cancer called gonadoblastoma.
Signs of Turner syndrome can start before birth, and they give parents some idea their baby might be born with this condition. An ultrasound of a baby with Turner syndrome may show heart and kidney problems or a buildup of fluid.
A DNA test using a blood sample from the mother can also screen for Turner syndrome before birth.
At birth or during infancy, your child might have several physical features that point to the condition. Those include swollen hands and feet or smaller than average height at birth.
Others include:
Other symptoms can include:
Turner syndrome in a fetus
"Turner syndrome may be diagnosed prenatally, though not always conclusively," according to Allison Lange, MD, Reproductive Endocrinologist at RMA. A doctor may suspect Turner syndrome in a fetus after doing a blood test called noninvasive prenatal testing (NIPT) that checks for genetic abnormalities.
Also, a fetal ultrasound may detect birth defects that can be associated with the syndrome. Those may include cystic hygroma (fluid-filled bump on the baby's neck), heart defects, kidney anomalies, or a short thigh bone (femur), which may suggest Turner syndrome.
A doctor can confirm the diagnosis with invasive testing, such as chorionic villous sampling (testing a sample of placenta tissue to check for genetic abnormalities) or amniocentesis (taking out a sample of the amniotic fluid protecting the fetus in your uterus to test for chromosomal abnormalities), Lange said.
Turner syndrome in babies
"Turner syndrome is more commonly suspected after delivery based on clinical features," said Lange. Babies with Turner syndrome may have:
Tiffany Kimbrough, MD, pediatrician and medical director of complex care at Children's Hospital of Richmond at VCU, said babies with Turner syndrome are at increased risk of certain malformations of their heart and kidneys. Heart disease is a serious part of Turner syndrome. Up to 50% of those with Turner syndrome have some form of cardiac malformation.
Hearing loss (sensorineural), which is either present at birth or worsens over time, is also common in babies with Turner syndrome.
Other conditions linked to Turner syndrome
If you have Turner syndrome, you may be more likely to have health conditions such as heart disease and bone problems. But that's not always the case.
Heart conditions. With Turner syndrome, you may have potentially life-threatening heart and blood vessel problems. At least 50% of people with Turner Syndrome have a heart condition present at birth. You could also have other heart problems, such as high blood pressure and bicuspid aortic valve (BAV), where your aortic valve has two flaps or cusps instead of three.
Bone problems. Turner syndrome may increase your risk of bone diseases such as osteoporosis, scoliosis, and bone fractures.
Autoimmune conditions. With Turner syndrome, you have a higher risk of autoimmune conditions, in which your immune system mistakenly attacks your cells. These include inflammatory bowel disease (IBD), celiac disease, and Hashimoto's thyroid disease.
Hearing and vision problems. When you have Turner syndrome, you're likely to have problems with your ears and eyes. You might be more likely to have frequent middle ear infections, hearing loss, lazy eyes, crossed eyes, and drooping eyelids.
Kidney conditions. About 30%-40% of those with Turner syndrome have kidney and urinary system problems. You might have trouble peeing, or you might lack a kidney.
Metabolic syndrome. You may be at a higher risk for heart disease, obesity, type 2 diabetes, stroke, and other metabolic disorders when you have Turner syndrome.
Learning disabilities. Although you're intelligent, you might have learning disabilities, such as problems with visual-motor and visual-spatial skills. That can make everyday activities, such as driving, challenging.
Lymphedema. You might have swelling and puffiness in your hands, legs, and feet.
Mental health problems. Turner syndrome can be difficult to manage. You may face mental health distress such as anxiety, depression, stress, and self-esteem problems.
Turner syndrome can be linked to other health conditions, such as:
If an ultrasound shows something abnormal while you're pregnant, your doctor may want to examine your baby's chromosomes with a test called karyotype. This test compares chromosomes by lining them up. To get samples from you, your doctor may recommend:
If a diagnosis isn't made before or at birth, other lab tests that check hormones, thyroid function, and blood sugar can help diagnose it.
Because of the problems linked to Turner syndrome, your doctor may suggest tests for the kidneys, heart, and hearing.
Building your child's Turner syndrome care team
"When possible, patients with Turner syndrome should be cared for in a dedicated multidisciplinary clinic," Lange said.
Your child's care team should include various specialists, each with a specific role:
Those with Turner syndrome are at risk of vision and hearing abnormalities and will often be followed by specialists within these fields, Lange said. Neuropsychology and behavioral health services are essential to provide support and perform developmental and behavioral screenings, she added.
"Each child is an individual, and it's important to cultivate the team that you trust to care for your child and your family along your health care journey," Kimbrough said.
Medical care often calls for a team of specialists built around the specific needs of each person, as cases vary so widely.
There's no cure, but most people with Turner syndrome will take the same main therapies during childhood and the teen years. These are:
If you think your child has Turner syndrome, see their doctor as soon as possible for early confirmation. Early diagnosis allows for timely interventions and management of potential complications.
You or your child can also:
Connect with other people who live with Turner syndrome. Connecting with others with Turner syndrome can be helpful. Online forums or local groups, such as The Turner Syndrome Society of the United States, can offer a sense of belonging and shared experience.
Be educated about the condition. Learn about Turner syndrome so that you and your family can make informed health care decisions and advocate for yourselves.
Remain proactive with health care visits. Stay on top of appointments so that your child can get the most out of treatments. Regular health care visits are also crucial for monitoring any changes or improvements in their health.
Get professional mental health help. You or your child may benefit from talk therapy to address mental health problems linked to Turner syndrome, like low self-esteem, anxiety, and depression.
Caring for a child with Turner syndrome
Caring for a child with Turner syndrome requires attention and compassion, Lange said. Get medical help when you notice any unusual features or symptoms in your child. Regular visits to your child's pediatrician and endocrinologist help make sure they grow and develop properly.
"Children with Turner syndrome also need appropriate emotional support," Lange added. Working with a child therapist can help. Lange recommends encouraging your child's independence in daily activities while offering support when needed.
Because many children with Turner syndrome experience learning and physical challenges, they may also benefit from physical, occupational, and educational support as well, Lange said.
Take your child for learning disability screenings as early as age 1 or 2. Talk to their teachers about how to best help with their learning needs and meet any accommodations.
Turner syndrome and pregnancy
If you have Turner syndrome, you may have trouble getting pregnant, as your ovaries don't make viable oocytes (cells necessary for reproduction). If you're able to become pregnant, high blood pressure and gestational diabetes might be issues. You also might have issues such as preeclampsia.
Before pregnancy, see a maternal-fetal medicine specialist and cardiologist, Lange said. Your doctor may do a prepregnancy baseline cardiac imaging, which may help predict the risks of pregnancy-related complications.
"Throughout the pregnancy, expect close heart function, fetal growth, and maternal blood pressure monitoring. A delivery plan should be created in advance and involve a multidisciplinary team," Lange said.
Is Turner syndrome XO or XXY?
Turner syndrome is XO, meaning one of your X chromosomes is partly or completely missing. It happens in people assigned female at birth. XXY happens in people assigned male at birth, with a condition called Klinefelter syndrome.
Is Turner syndrome tied to autism?
People with Turner syndrome are four times more likely to have autism, some studies show.
Does everyone with Turner syndrome have a period?
No, most people with Turner syndrome don't have a period.
Why can't Turner syndrome be cured?
Turner syndrome can't be cured because it involves a problem with your genetic makeup.
Does Turner syndrome cause pain?
Turner syndrome on its own is unlikely to cause pain. But it might increase your risk for health problems that cause pain, like bone fractures and kidney diseases.
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