Phenylketonuria
PKU; Neonatal phenylketonuria
Phenylketonuria (PKU) is a rare condition in which a baby is born without the ability to properly break down an
amino acid called phenylalanine.
Causes, incidence, and risk factors
Phenylketonuria (PKU) is inherited, which means it is passed down through families. Both parents must pass on
the defective gene in order for a baby to have the condition. This is called an autosomal recessive trait.
Babies with PKU are missing an enzyme called phenylalanine hydroxylase, which is needed to break down an
essential amino acid called phenylalanine. The substance is found in foods that contain protein.
Without the enzyme, levels of phenylalanine and two closely-related substances build up in the body. These
substances are harmful to the central nervous system and cause brain damage.
Symptoms
Phenylalanine plays a role in the body's production of melanin, the pigment responsible for skin and hair color.
Therefore, infants with the condition often have lighter skin, hair, and eyes than brothers or sisters without the
disease.
Other symptoms may include:
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Delayed mental and social skills
Head size significantly below normal
Hyperactivity
Jerking movements of the arms or legs
Mental retardation
Seizures
Skin rashes
Tremors
Unusual positioning of hands
If the condition is untreated or foods containing phenylalanine are not avoided, a "mousy" or "musty" odor may
be detected on the breath and skin and in urine. The unusual odor is due to a build up of phenylalanine
substances in the body.
Signs and tests
PKU can be easily detected with a simple blood test. All states in the US require a PKU screening test for all
newborns as part of the newborn screening panel. The test is generally done by taking a few drops of blood
from the baby before the baby leaves the hospital.
If the initial screening test is positive, further blood and urine tests are required to confirm the diagnosis.
Treatment
PKU is a treatable disease. Treatment involves a diet that is extremely low in phenylalanine, particularly when
the child is growing. The diet must be strictly followed. This requires close supervision by a registered dietitian
or doctor, and cooperation of the parent and child. Those who continue the diet into adulthood have better
physical and mental health. “Diet for life” has become the standard recommended by most experts. This is
especially important before conception and throughout pregnancy.
Phenylalanine occurs in significant amounts in milk, eggs, and other common foods. The artificial sweetener
NutraSweet (aspartame) also contains phenylalanine. Any products containing aspartame should be avoided.
A special infant formula called Lofenalac is made for infants with PKU. It can be used throughout life as a
protein source that is extremely low in phenylalanine and balanced for the remaining essential amino acids.
Taking supplements such as fish oil to replace the long chain fatty acids missing from a standard phenylalaninefree diet may help improve neurologic development, including fine motor coordination. Other specific
supplements, such as iron or carnitine, may be needed.
Expectations (prognosis)
The outcome is expected to be very good if the diet is closely followed, starting shortly after the child's birth. If
treatment is delayed or the condition remains untreated, brain damage will occur. School functioning may be
mildly impaired.
If proteins containing phenylalanine are not avoided, PKU can lead to mental retardation by the end of the first
year of life.
Complications
Severe mental retardation occurs if the disorder is untreated. ADHD (attention-deficit hyperactivity disorder)
appears to be the most common problem seen in those who do not stick to a very low-phenylalanine diet.
Prevention
An enzyme assay can determine if parents carry the gene for PKU. Chorionic villus sampling can be done
during pregnancy to screen the unborn baby for PKU.
It is very important that women with PKU closely follow a strict low-phenylalanine diet both before becoming
pregnant and throughout the pregnancy, since build-up of this substance will damage the developing baby even
if the child has not inherited the defective gene.
Albinism
Albinism is a defect of melanin production that results in little or no color (pigment) in the skin, hair, and eyes.
Causes, incidence, and risk factors
Albinism occurs when one of several genetic defects makes the body unable to produce or distribute melanin, a
natural substance that gives color to your hair, skin, and iris of the eye.
The defects may be passed down through families.
There are two main types of albinism:
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Type 1 albinism is caused by defects that affect production of the pigment, melanin.
Type 2 albinism is due to a defect in the "P" gene. People with this type have slight coloring at birth.
The most severe form of albinism is called oculocutaneous albinism. People with this type of albinism have
white or pink hair, skin, and iris color, as well as vision problems.
Another type of albism, called ocular albinism type 1 (OA1), affects only the eyes. The person's skin and eye
colors are usually in the normal range. However, an eye exam will show that there is no coloring in the back of
the eye (retina).
Hermansky-Pudlak syndrome (HPS) is a form of albinism caused by a single gene. It can occur with a bleeding
disorder, as well as with lung and bowel diseases.
Other complex diseases may lead to loss of coloring in only a certain area (localized albinism). These
conditions include:
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Chediak-Higashi syndrome (lack of coloring all over the skin, but not complete)
Tuberous sclerosis (small areas without skin coloring )
Waardenburg syndrome (often a lock of hair that grows on the forehead, or no coloring in one or both
irises)
Symptoms
A person with albinism will have one of the following symptoms:
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Absence of color in the hair, skin, or iris of the eye
Lighter than normal skin and hair
Patchy, missing skin color
Many forms of albinism are associated with the following symptoms:
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Crossed eyes (strabismus)
Light sensitivity (photophobia)
Rapid eye movements (nystagmus)
Vision problems, or functional blindness
Signs and tests
Genetic testing offers the most accurate way to diagnose albinism. Such testing is helpful if you have a family
history of albinism. It is also useful for certain groups of people who are known to get the disease.
Your doctor may also diagnose the condition based on the appearance of your skin, hair, and eyes. An
ophthalmologist should perform a electroretinogram test, which can reveal vision problems related to albinism.
A visual evoked potentials test can be very useful when the diagnosis is uncertain.
Treatment
The goal of treatment is to relieve symptoms. Treatment depends on the severity of the disorder.
Treatment involves protecting the skin and eyes from the sun:
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Reduce sunburn risk by avoiding the sun, using sunscreen, and covering up completely with clothing
when exposed to the sun.
Sunscreen should have a high sun protection factor (SPF).
Sunglasses (UV protected) may relieve light sensitivity.
Glasses are often prescribed to correct vision problems and eye position. Eye muscle surgery is sometimes
recommended to correct abnormal eye movements (nystagmus).
Expectations (prognosis)
Albinism does not usually affect lifespan. Hermansky-Pudlak syndrome can, however, shorten lifespan due to
lung disease or bleeding problems.
People with albinism may be limited in their activities because they can't tolerate the sun.
Complications
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Decreased vision, blindness
Skin cancer
Down Syndrome
The human body is made of cells. All cells contain a center, called a nucleus, in which genes are stored. Genes,
which carry the codes responsible for all our inherited characteristics, are grouped along rod-like structures
called chromosomes. Normally, the nucleus of each cell contains 23 pairs of chromosomes, half of which are
inherited from each parent. Down syndrome occurs when some or all of a person’s cells have an extra full or
partial copy of chromosome 21.
The most common form of Down syndrome is known as Trisomy 21. Individuals with Trisomy 21 have 47
chromosomes instead of the usual 46 in each of their cells. The condition results from an error in cell division
called non-disjunction. Prior to or at conception, a pair of 21st chromosomes in either the sperm or the egg fails
to separate.
As the embryo develops, the extra chromosome is replicated in every cell of the body. This error in cell division
is responsible for 95 percent of all cases of Down syndrome. Having an extra copy of this chromosome means
that each gene may be producing more protein product than normal. Cells seem to tolerate this better than
having not enough protein, or having altered protein due to a mutation in the DNA sequence. The condition
leads to impairments in both cognitive ability and physical growth that range from mild to moderate
developmental disabilities. Through a series of screenings and tests,
Down syndrome can be detected before and after a baby is born. The only factor known to affect the probability
of having a baby with Down syndrome is maternal age. That is, less than one in 1,000 pregnancies for mothers
less than 30 years of age results in a baby with Down syndrome. For mothers who are 44 years of age, about 1
in 35 pregnancies results in a baby with Down syndrome. Because younger women generally have more
children, about 75% – 80% of children with Down syndrome are born to younger women.
How do people get Down syndrome?
Down syndrome occurs because of an abnormality characterized by an extra copy of genetic material on all or
part of the 21st chromosome. Every cell in the body contains genes that are grouped along chromosomes in the
cell’s nucleus or center. There are normally 46 chromosomes in each cell, 23 inherited from your mother and 23
from your father. When some or all of a person’s cells have an extra full or partial copy of chromosome 21, the
result is Down syndrome.
Down syndrome is typically caused by what is called nondisjunction. If a pair of number 21 chromosomes fails
to separate during the formation of an egg (or sperm), this is referred to as nondisjunction. When that egg unites
with a normal sperm to form an embryo, that embryo ends up with three copies of chromosome 21 instead of
the normal two. The extra chromosome is then copied in every cell of the baby’s body. Nondisjunction events
seem to occur more frequently in older women. This may explain why the risk of having a baby with Down
syndrome is greater among mothers age 35 and older.
What are the symptoms of Down syndrome?
Despite the variability in Down syndrome, individuals with Down syndrome have a widely recognized
characteristic appearance. Typical facial features include a flattened nose, small mouth, protruding tongue,
small ears, and upward slanting eyes. The inner corner of the eyes may have a rounded fold of skin (epicanthal
fold). The hands are short and broad with short fingers, and may have a single palmar crease. White spots on the
colored part of the eye called Brushfield spots may be present. Babies with Down syndrome often have
decreased muscle tone at birth. Normal growth and development is usually delayed and often individuals with
Down syndrome don’t reach the average height or developmental milestones of unaffected individual.
How do doctors diagnose Down syndrome?
Three types of tests check for Down syndrome during a woman’s pregnancy: screening and diagnostic tests.
Screening tests identify a mother who is likely carrying a baby with Down syndrome. The most common
screening tests are the Triple Screen and the Alpha-Fetoprotein Plus. These tests measure levels of certain
substances in the blood.
Alternatively, ultrasounds (which use sound waves to look inside the mother’s uterus) allow the doctor to
examine the fetus in the womb for the physical signs of Down syndrome. To confirm a positive result identified
in a screening test, one of the following diagnostic tests can be performed: chronic villus sampling (CVS),
amniocentesis. Each takes a sample from the placenta, amniotic fluid, or umbilical cord, respectively, to
examine the baby’s chromosomes and determine if he or she has an extra chromosome 21.
If Down syndrome is not diagnosed in the womb, doctors can usually recognize it after the baby is born by the
distinctive facial features. The diagnosis is confirmed with a karyotype – an examination of the baby’s
chromosomes.
Amniocentesis, chorionic villus and ultrasound are the three primary procedures for diagnostic testing, which
can identify certain abnormalities in the fetus.
Amniocentesis is used most commonly to identify chromosomal problems, such as Down syndrome. When the fetus
is known to be at risk, it can detect other genetic diseases like cystic fibrosis, Tay-Sachs disease and sickle cell
disease. An amniocentesis procedure for genetic testing is typically performed between 15 and 20 weeks of
pregnancy. Under ultrasound guidance, a needle is inserted through the abdomen to remove a small amount of
amniotic fluid. The cells from the fluid are then cultured and a karyotype analysis — an analysis of the chromosomal
make-up of the cells — is performed. It takes about two weeks to receive the results of the test.Amniocentesis
detects most chromosomal disorders, such as Down syndrome, with a high degree of accuracy. Testing for other
genetic diseases, such as Tay-Sachs disease, is not routinely performed but can be detected through specialized
testing if your fetus is known to be at risk. Testing for neural tube defects, such as spina bifida, also can be
performed. There is a small risk of miscarriage as a result of amniocentesis — about 1 in 100 or less. Miscarriage
rates for procedures performed at UCSF Medical Center are less than 1 in 350.
Interesting facts about Down syndrome
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Down syndrome is really the only trisomy compatible with life. Only two other trisomies have been observed in
babies born alive (trisomies 13 and 18), but babies born with these trisomies have only a 5% chance of surviving
longer than one year.
In 90% of Trisomy 21 cases, the additional chromosome comes from the mother’s egg rather than the father’s
sperm.
Down syndrome is the most common genetic disorder caused by a chromosomal abnormality. It affects 1 out of
every 800 to 1,000 babies.
Down syndrome was originally described in 1866 by John Langdon Down. It wasn’t until 1959 that a French
doctor, named Jerome Lejeune, discovered it was caused by the inheritance of an extra chromosome
Klinefelter Syndrome
What is Klinefelter syndrome?
Klinefelter syndrome, also known as the XXY condition, is a term used to describe males who have an extra X
chromosome in most of their cells. Instead of having the usual XY chromosome pattern that most males have,
these men have an XXY pattern.
Klinefelter syndrome is named after Dr. Henry Klinefelter, who first described a group of symptoms found in
some men with the extra X chromosome. Even though all men with Klinefelter syndrome have the extra X
chromosome, not every XXY male has all of those symptoms.
Because not every male with an XXY pattern has all the symptoms of Klinefelter syndrome, it is common to
use the term XXY male to describe these men, or XXY condition to describe the symptoms.
Scientists believe the XXY condition is one of the most common chromosome abnormalities in humans. About
one of every 500 males has an extra X chromosome, but many don’t have any symptoms.
What are the symptoms of the XXY condition?
Not all males with the condition have the same symptoms or to the same degree. Symptoms depend on how
many XXY cells a man has, how much testosterone is in his body, and his age when the condition is diagnosed.
The XXY condition can affect three main areas of development:
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Physical development: As babies, many XXY males have weak muscles and reduced strength. They
may sit up, crawl, and walk later than other infants. After about age four, XXY males tend to be taller
and may have less muscle control and coordination than other boys their age.
As XXY males enter puberty, they often don’t make as much testosterone as other boys. This can lead
to a taller, less muscular body, less facial and body hair, and broader hips than other boys. As teens,
XXY males may have larger breasts, weaker bones, and a lower energy level than other boys.
By adulthood, XXY males look similar to males without the condition, although they are often taller.
They are also more likely than other men to have certain health problems, such as autoimmune
disorders, breast cancer, vein diseases, osteoporosis, and tooth decay.
XXY males can have normal sex lives, but they usually make little or no sperm. Between 95 percent
and 99 percent of XXY males are infertile because their bodies don’t make a lot of sperm.
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Language development: As boys, between 25 percent and 85 percent of XXY males have some kind of
language problem, such as learning to talk late, trouble using language to express thoughts and needs,
problems reading, and trouble processing what they hear.
As adults, XXY males may have a harder time doing work that involves reading and writing, but most
hold jobs and have successful careers.
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Social development: As babies, XXY males tend to be quiet and undemanding. As they get older, they
are usually quieter, less self-confident, less active, and more helpful and obedient than other boys.
As teens, XXY males tend to be quiet and shy. They may struggle in school and sports, meaning they
may have more trouble “fitting in” with other kids.
However, as adults, XXY males live lives similar to men without the condition; they have friends,
families, and normal social relationships.
What are the treatments for the XXY condition?
The XXY chromosome pattern can not be changed. But, there are a variety of ways to treat the symptoms of the
XXY condition.
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Educational treatments – As children, many XXY males qualify for special services to help them in
school. Teachers can also help by using certain methods in the classroom, such as breaking bigger tasks
into small steps.
Therapeutic options – A variety of therapists, such as physical, speech, occupational, behavioral, mental
health, and family therapists, can often help reduce or eliminate some of the symptoms of the XXY
condition, such as poor muscle tone, speech or language problems, or low self-confidence.
Medical treatments – Testosterone replacement therapy (TRT) can greatly help XXY males get their
testosterone levels into normal range. Having a more normal testosterone level can help develop bigger
muscles, deepen the voice, and grow facial and body hair. TRT often starts when a boy reaches puberty.
Some XXY males can also benefit from fertility treatment to help them father children.
What are the genetic changes related to Klinefelter syndrome?
Klinefelter syndrome is a condition related to the X chromosome and Y chromosome (the sex chromosomes).
People typically have two sex chromosomes in each cell: females have two X chromosomes (46,XX), and males
have one X and one Y chromosome (46,XY). Most often, Klinefelter syndrome results from the presence of a
single extra copy of the X chromosome in each of a male's cells (47,XXY). Extra copies of genes on the X
chromosome interfere with male sexual development, preventing the testes from functioning normally and
reducing the levels of testosterone.
Some males with Klinefelter syndrome have the extra X chromosome in only some of their cells; in these
individuals, the condition is described as mosaic Klinefelter syndrome (46,XY/47,XXY). Individuals with
mosaic Klinefelter syndrome may have milder signs and symptoms depending on how many cells have an
additional X chromosome.
Variants of Klinefelter syndrome are caused by several extra copies of the X chromosome in all of the body's
cells. As the number of extra sex chromosomes increases, so does the risk of intellectual disability, birth
defects, and other health issues.
Can Klinefelter syndrome be inherited?
This condition is not inherited; it usually occurs as a random event during the formation of reproductive cells
(eggs and sperm). An error in cell division called nondisjunction results in a reproductive cell with an abnormal
number of chromosomes. For example, an egg or sperm cell may gain one or more extra copies of the X
chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic
makeup of a child, the child will have one or more extra X chromosomes in each of the body's cells.
Turner syndrome
Turner syndrome is a genetic condition in which a female does not have the usual pair of two X chromosomes.
Causes, incidence, and risk factors
Humans have 46 chromosomes. Chromosomes contain all of your genes and DNA, the building blocks of the
body. Two of these chromosomes, the sex chromosomes, determine if you become a boy or a girl. Females
normally have two of the same sex chromosomes, written as XX. Males have an X and a Y chromosome
(written as XY).
In Turner syndrome, cells are missing all or part of an X chromosome. The condition only occurs in females.
Most commonly, the female patient has only one X chromosome. Others may have two X chromosomes, but
one of them is incomplete. Sometimes, a female has some cells with two X chromosomes, but other cells have
only one.
Turner syndrome occurs in about 1 out of 2,000 live births.
Symptoms
Possible symptoms in young infants include:
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Swollen hands and feet
Wide and webbed neck
A combination of the following symptoms may be seen in older females:
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Absent or incomplete development at puberty, including sparse pubic hair and small breasts
Broad, flat chest shaped like a shield
Drooping eyelids
Dry eyes
Infertility
No periods (absent menstruation)
Short height
Vaginal dryness, can lead to painful intercourse
Signs and tests
Turner syndrome can be diagnosed at any stage of life. It may be diagnosed before birth if chromosome analysis
is done during prenatal testing.
The doctor will perform a physical exam and look for signs of underdevelopment. Infants with Turner
syndrome often have swollen hands and feet.
The following tests may be performed:
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Blood hormone levels (luteinizing hormone and follicle stimulating hormone)
Echocardiogram
Karyotyping
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MRI of the chest
Ultrasound of reproductive organs and kidneys
Pelvic exam
Turner syndrome may also alter various estrogen levels in the blood and urine.
Treatment
Growth hormone may help a child with Turner syndrome grow taller. Estrogen replacement therapy is often
started when the girl is 12 or 13 years old. This helps trigger the growth of breasts, pubic hair, and other sexual
characteristics.
Women with Turner syndrome who wish to become pregnant may consider using a donor egg.
Support Groups
For additional information and resources, see:
Turner Syndrome Society -- www.turnersyndrome.org
Expectations (prognosis)
Those with Turner syndrome can have a normal life when carefully monitored by their doctor.
Complications
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Arthritis
Cataracts
Diabetes
Hashimoto's thyroiditis
Heart defects
High blood pressure
Kidney problems
Middle ear infections
Obesity
Scoliosis (in adolescence)