Disorders

Chromosomes are structures within cells that contain a person's genes. Abnormalities in chromosomes are always genetic abnormalities. Some genetic abnormalities affect the genes, but do not alter the structure of the chromosomes. Thus, doctors often discuss chromosomal abnormalities separately from the broader category of genetic abnormalities. Some genetic abnormalities, such as sickle cell disease and cystic fibrosis, are very common.

A person normally has 23 pairs of chromosomes, each containing hundreds of genes. The sex chromosomes are one of these pairs of chromosomes. Normal people have 2 sex chromosomes; each is either an X or a Y chromosome. Normal females have two X chromosomes (XX), and normal males have one X and one Y chromosome (XY).

Chromosomal abnormalities can affect any chromosome, including the sex chromosomes. A chromosomal or other genetic abnormality can affect the number of chromosomes, the structure of certain chromosomes, or the composition of chromosomes (for example, genetic material from one chromosome may be attached to another). If the material found in chromosomes is balanced so that the expected amount is found in each cell, no abnormalities occur. If too much (addition) or too little (deletion) genetic material is found within each cell, abnormalities occur. These abnormalities can have profound physical effects.

The older a pregnant woman is, the greater the chance that her fetus will have a chromosomal abnormality. The chance of chromosomal abnormalities increases by a barely noticeable degree if the father is older. A marriage between close relatives increases the chance of developing some genetic abnormalities, but usually not chromosomal abnormalities.

Chromosomal abnormalities can cause a wide range of abnormalities or effects, usually birth defects or death of the embryo or fetus before birth. Genetic abnormalities can cause birth defects or diseases (for example, sickle cell disease) or have many different effects.

A person's chromosomes can be analyzed with a sample of blood. A fetus can be tested for chromosomal abnormalities before birth, for example, using amniocentesis or chorionic villus sampling. If the fetus is found to have a chromosomal abnormality, further tests may be performed to detect specific birth defects. Although chromosomal abnormalities cannot be corrected, some of the defects can sometimes be prevented or treated.

When Part of a Chromosome Is Missing
A number of syndromes can occur in infants who are missing part of a chromosome. These syndromes are called chromosome deletion syndromes.

In the rare cri du chat syndrome (cat's cry syndrome, 5p minus syndrome), part of chromosome 5 is missing. An infant with this syndrome is usually underweight at birth; has a small head with many abnormal features, including a round face, small jaw, wide nose, widely separated eyes, and ears set low in the head; and has a high-pitched cry that sounds like a kitten crying. Often the infant seems limp. The high-pitched cry occurs immediately after birth, lasts several weeks, and then disappears. Heart defects are common. Mental and physical development are greatly retarded. Despite these abnormalities, many children with cri du chat syndrome survive to adulthood.

In Prader-Willi syndrome, another chromosomal deletion syndrome, mental retardation is common. Many symptoms vary according to the child's age. Newborns with the defect feel limp, feed poorly, and gain weight slowly. Eventually these symptoms resolve. Then, between the ages of 1 and 6, appetite increases, often becoming insatiable. Obsessive-compulsive behaviors are common. Weight gain is excessive, which can lead to other health problems. Obesity can be severe enough to require gastric bypass surgery.

Down Syndrome

Down syndrome (trisomy 21) is a chromosomal disorder resulting in mental retardation and physical abnormalities.
An extra chromosome, making three of a kind, is called trisomy. The most common trisomy in a newborn is trisomy 21 (three copies of chromosome 21). Trisomy 21 causes about 95% of the cases of Down syndrome. Older mothers, especially those older than 35, contribute an extra chromosome more often than do younger mothers. As a result, they more often bear children with Down syndrome. However, the extra chromosome may come from the father.
 
Symptoms
In Down syndrome, physical and mental development is delayed. Infants with Down syndrome tend to be quiet, passive, and have somewhat limp muscles. The intelligence quotient (IQ) among children with Down syndrome varies but averages about 50, compared with normal children, whose average IQ is 100. Children with Down syndrome have better visual motor skills (such as drawing) than skills that require hearing. Thus, their language skills typically develop slowly. Early intervention with educational and other services improves the functioning of young children with Down syndrome.

Children with Down syndrome tend to have a small head, a face that is broad and flat with slanting eyes and a short nose. The tongue is large. The ears are small and set low in the head. The hands are short and broad, with a single crease across the palm. The fingers are short; the fifth finger, which often has two instead of three sections, curves inward. A space is visible between the first and second toes.
Children with Down syndrome often have heart defects. Many people with Down syndrome develop thyroid disease. They are prone to hearing problems because of recurring ear infections and the associated accumulation of inner ear fluid (serous otitis). They are also prone to vision problems because of problems in their corneas and lenses. Many people with Down syndrome develop symptoms of Alzheimer-like dementia in their 30s, such as memory loss, further lowering of intellect, and personality changes.

Diagnosis
The diagnosis of Down syndrome can often be made before birth. An infant with Down syndrome has a physical appearance that suggests the diagnosis. A doctor confirms the diagnosis by testing the infant's chromosomes for trisomy 21 or other disorders of the 21st chromosome. After the diagnosis is made, doctors use tests, such as ultrasound and blood tests, along with examinations by specialists, to detect abnormalities associated with Down syndrome. Treating abnormalities that are detected can often prevent them from impairing health.

Prognosis
Most children with Down syndrome survive to adulthood. Life expectancy for a child with Down syndrome with mild or moderate retardation is 55 years and with profound mental retardation is 45 years. Many have progressively worsening mental functioning. Heart abnormalities are often treatable with drugs or surgery. Heart disease and leukemia account for most deaths among children with Down syndrome.

Fragile X Syndrome

Fragile X syndrome is a genetic abnormality in an X chromosome that leads to delayed development and other symptoms.
The symptoms of fragile X syndrome are caused by abnormalities in DNA on the X chromosome. Usually, affected boys inherit the condition from their mothers.

Many children with the syndrome have normal intelligence. However, the syndrome is the most commonly diagnosed genetic cause of mental retardation besides Down syndrome. The severity of symptoms, including mental retardation, is worse in boys than in girls with the disorder. Symptoms, which are often subtle, include delayed development; large, protuberant ears; a prominent chin and forehead; and, in boys, large testes (most apparent after puberty). The joints may be abnormally flexible, and heart disease (mitral valve prolapse) may occur. Features of autism may develop. Women may experience menopause in their mid 30s.

The presence of abnormal DNA on the fragile X chromosome can be detected by tests before or after birth. The greater the number of abnormal repetitions of DNA found, the more likely the child will have symptoms.

Early intervention, including speech and language therapy and occupational therapy, can help children with fragile X syndrome to maximize their abilities. Stimulants, antidepressants, and antianxiety drugs may be beneficial for some children.

Klinefelter Syndrome

Klinefelter syndrome is a disorder in which male infants are born with an extra X chromosome (XXY).
Klinefelter syndrome is relatively common. Most boys with Klinefelter syndrome have normal or slightly decreased intelligence. Many have speech and reading disabilities and difficulties with planning. Most have problems with language skills. Early problems with language may lead to problems with social interactions that affect behavior, and these children often get into trouble at school. Although their physical characteristics can vary greatly, most are tall with long arms but otherwise normal in appearance.

Puberty usually occurs at the normal time, but the testes remain small. At puberty, growth of facial hair is often sparse, and the breasts may enlarge somewhat (gynecomastia). Men and boys with the syndrome are usually infertile. Men with Klinefelter syndrome develop diabetes mellitus, chronic lung disease, varicose veins, hypothyroidism, and breast cancer more often than other men.
The syndrome is usually first suspected at puberty, when most of the symptoms develop. Analysis of the chromosomes confirms the diagnosis.

Boys with Klinefelter syndrome usually benefit from speech and language therapy and eventually can do well in school. Some men benefit by taking supplemental male hormones such as testosterone. The hormones improve bone density, making fractures less likely, and stimulate development of a more masculine appearance.

Long QT Syndrome

Long QT syndrome is an abnormality of the heart's electrical system, which may cause loss of consciousness or sudden death.

Long QT syndrome may affect as many as 1 of 7,000 people. In the United States, it may cause sudden death in 3,000 to 4,000 children and young adults each year. In children, this disorder is usually due to a genetic abnormality. A person with the disorder may have family members who died suddenly and inexplicably. In most adults, long QT syndrome is caused by use of a drug or a disorder.
People who have long QT syndrome are predisposed to developing an unusually fast heart rate, which often occurs during physical activity or emotional excitement. When the heart rate is too fast, the brain may not receive enough blood. The result is loss of consciousness. Some people with long QT syndrome are also born deaf. But about one third of people have no symptoms. Long QT syndrome can cause sudden death at a young age.

Doctors may recommend electrocardiography (ECG ) for children or young adults who have suddenly and inexplicably lost consciousness. The procedure may be performed with the person at rest or after receiving intravenous drugs or the person may be asked to walk on a treadmill or pedal an exercise bicycle in a procedure called exercise stress testing.

Beta-blockers are effective for most children and adults. Some adults may benefit from mexiletine, an antiarrhythmic drug. For children and adults who do not respond to drugs, a pacemaker or a combination pacemaker-internal defibrillator may be tried. An internal defibrillator can shock the heart, reviving the person, whenever the heart develops a lethal rhythm abnormality. Occasionally, as an alternative, a nerve in the neck is cut in a procedure called cervicothoracic sympathectomy. Cutting this nerve can help prevent the fast heart rate that causes sudden death.

Noonan Syndrome

Noonan syndrome is a genetic defect that causes a number of physical abnormalities, usually including short stature, heart defects, and an abnormal appearance.
Noonan syndrome can be inherited or can develop unpredictably in children whose parents have normal genes. Although children with the syndrome have normal chromosomal structure, they have many characteristics typical of Turner syndrome. In the past, Noonan syndrome was called "male Turner syndrome." Boys or girls can be affected. The gene responsible for Noonan syndrome has been localized to chromosome 12.

Symptoms may include webbing of the neck, low-set ears, droopy eyelids, short stature, shortened fourth (ring) fingers, a high-arched palate, and heart and blood vessel abnormalities. Intelligence may be impaired. Most affected people are short. Boys may have underdeveloped or undescended testes. In girls, the ovaries may be underactive or stop working. Puberty may be delayed, and infertility may develop.

Growth may be improved by treatment with growth hormone. After satisfactory growth, testosterone treatment may help boys whose testes are underdeveloped. Testosterone stimulates the development of a more masculine appearance.

X Syndrome

Triple X (trisomy X) syndrome is a rare disorder in which female infants are born with three X chromosomes.
Girls with triple X syndrome tend to have slightly lower intelligence and particular problems with verbal skills. Sometimes the syndrome causes infertility, although some women with triple X syndrome have given birth to physically normal children who had normal chromosomes.

Extremely rare cases of infants with four or even five X chromosomes have been identified. The more X chromosomes the girl has, the greater the chance of mental retardation and physical abnormalities.

Turner Syndrome

In Turner syndrome (gonadal dysgenesis), girls are born with one of the two X chromosomes partially or completely missing.
Many newborns with Turner syndrome have swelling (lymphedema) on the backs of their hands and tops of their feet. Swelling or loose folds of skin are often evident over the back of the neck. Many other abnormalities often develop, including a webbed neck (wide skin attachment between the neck and shoulders), a low hairline at the back of the neck, a broad chest with wide-spaced nipples, and poorly developed nails.

As a girl with Turner syndrome gets older, she has no menstrual periods (amenorrhea), and the breasts, vagina, and labia remain childlike rather than undergoing the changes of puberty. The ovaries usually do not contain developing eggs. A girl or woman with Turner syndrome is virtually always short; obesity is common.

Other disorders often develop. Heart defects include narrowing of part of the aorta (coarctation of the aorta). Kidney and eye defects, diabetes mellitus, and thyroid diseases are common. Occasionally, abnormal blood vessels in the intestine cause bleeding.

Many girls with Turner syndrome have difficulty in assessing visual and spatial relationships and have problems with planning and attention. They tend to score poorly on certain performance tests and in mathematics, even if they achieve average or above-average scores on verbal intelligence tests. Mental retardation is uncommon.

A doctor may suspect the diagnosis because of the newborn's abnormal appearance. However, suspicion often does not develop until the teenage years, when the girl fails to mature sexually. Analysis of the chromosomes confirms the diagnosis.

Treatment with a hormone normally secreted from the brain (growth hormone) can stimulate growth. Treatment with the female hormone estrogen is usually not started until after satisfactory growth has been achieved. Estrogen treatment may improve planning, attention, and assessment of visual and spatial relationships as well as stimulating sexual maturation.

XYY Syndrome

The XYY syndrome is a disorder in which a male infant is born with an extra Y chromosome.
Boys with XYY syndrome tend to be tall and have difficulties with language. The IQ tends to be slightly lower than that of other family members. Learning disabilities, attention deficit disorder, and minor behavioral disorders can develop. The XYY syndrome was once thought to cause aggressive or violent criminal behavior, but this theory has been disproved.