Trisomy 8 mosaicism syndrome

Definition

Trisomy 8 is defined as the presence of three full copies of chromosome 8 in all of a person's cells. Mosaic trisomy 8 describes the situation that occurs when only a portion of these cells contains three copies of chromosome 8, while others contain the usual two copies of that chromosome. For example, people with mosaic trisomy 8 may have cells in their blood and other tissues with the normal chromosome number, but may have cells in their skin with trisomy 8.

Description

The condition is sometimes also referred to as trisomy 8 mosaicism syndrome (T8mS) and mosaic Warkany syndrome. Common characteristics of T8mS are distinct facial features, including low-set or abnormally shaped ears and a bulbous-tipped nose, eye abnormalities like strabismus and corneal clouding, bone and tissue abnormalities, various structural heart problems, palate abnormalities, hydronephrosis, cryptorchidism, mild to moderate mental delays, and deep hand and feet creases. These characteristics tend to vary widely from person to person.

Genetic profile

The presence of three copies of a chromosome typically arises from a process called nondisjunction. This happens during the very complex process of cell division. It can occur during meiosis, the process of cell division within the sperm and eggs prior to fertilization. It can also happen during mitosis, the process of cell division in the zygote after fertilization.

A fertilized human zygote usually has 46 chromosomes in total. In mitosis, the zygote's cells divide and duplicate themselves evenly, keeping the chromosome number the same in all of the duplicated cells. If nondisjunction occurs, a pair of chromosomes does not divide evenly. This can result in too few chromosomes in some cells, which is called monosomy. It also results in too many chromosomes in other cells. If nondisjunction involves chromosome 8, it can lead to trisomy 8.

When nondisjunction happens during mitosis and causes trisomy 8, it only causes trisomy 8 in a portion of that individual's cells. A single cell then has trisomy 8, and these continue to duplicate themselves in certain organs and tissues. At the same time, cells with the normal number of chromosomes duplicate themselves in other organs and tissues. In the end, the affected person has a combination of cells with the normal chromosome number and those with trisomy 8, which is T8mS. This may occur in varying different tissues of that person and the exact ones cannot be predicted. Depending on when the nondisjunction happened, the person may have few or many cells with trisomy 8.

Nondisjunction is a cell division error that occurs by chance. Thus, no parent has control over this process and cannot influence the number of chromosomes their child receives at, or after, conception. In turn, T8mS is considered an unpredictable event that typically carries a very low recurrence risk for that person's parents and family. Unlike other conditions involving nondisjunction, like Down syndrome , T8mS has not been strongly associated with a mother's or father's age at conception.

Most people with T8mS do not have a family history of the condition, since it usually occurs by chance.

Demographics

Full trisomy 8 occurs in about 0.7% of spontaneous miscarriages. It is estimated to occur in about 0.1% of recognized pregnancies. When seen at birth, it is almost always due to mosaic trisomy 8 as opposed to full trisomy 8. The exact incidence of live-born children with T8mS was not known as of 2005, but a study by Nielsen, et al., in 1991 found one child with the condition among 34,910 newborns.

T8mS has been reported worldwide, being slightly more common in males than in females.

Signs and symptoms

Characteristics of T8mS vary. In other chromosome mosaicism conditions, more severe symptoms and a worse prognosis are associated with a larger proportion of cells with an abnormal chromosome number being present. Interestingly, that does not seem to be the case in T8mS. The percentage of cells with trisomy 8 does not appear to correlate with the types of symptoms the affected person experiences.

The creases on the palms and soles of people with T8mS are the most unique characteristic of the condition. On the palms there may be more arches than usual on the fingertips and a single crease running across the palm. The creases are often deep and vertical, with a furrowed appearance, on the soles of the feet.

People with T8mS often have distinct facial characteristics. This can include a wide upturned nose, thicker and downturned lower lip, and low-set and prominent ears that may not be shaped in the usual way. They may also have abnormalities of the palate, including a cleft (opening) or highly arched palate.

Mental retardation can occur with the condition, and the degree of mental delays varies from mild to moderate.

Other findings in T8mS can include those of the bone and tissues. These may be narrow shoulders, absent knee caps, abnormally shaped toes, tighter joints, slender palms, extra or missing ribs, and curving of the spine.

Eye abnormalities are seen in T8mS, and the two most common findings are corneal clouding and strabismus where an eye turns in. These may or may not cause significant vision problems and require treatment. More rare eye problems can include a smaller eye size, smaller eye openings, droopy eyelids, wide-set eyes, tilted optic discs, nearsightedness, retinal abnormalities, and epicanthic folds.

Occasional other characteristics can include structural heart problems, hydronephrosis, underdeveloped genitalia, cancer , and testes that have not descended into the scrotal sacs.

Diagnosis

Suspicions about T8mS are usually based on a child being born with unique characteristics, since there usually is no reason one would suspect it, such as a family history of the condition. Blood chromosome testing is widely available to diagnose chromosome abnormalities. If enough cells are carefully analyzed in the laboratory, T8mS can often be found in a blood sample.

In situations where a child with multiple characteristics has normal blood chromosome results, other tissues like the skin can be studied for its chromosome makeup. A trained physician can do a brief procedure called a skin biopsy to obtain a small skin sample. During this, the physician takes a pencil eraser-sized piece of skin from a child's arm or back. Sometimes this testing reveals the presence of trisomy 18 in skin cells, which would confirm a diagnosis of T8mS.

Many characteristics of T8mS will not be seen during a pregnancy. However, a woman may be offered a routine prenatal chromosome testing for other reasons, such as her age or family history. A chorionic villus sampling (CVS) or amniocentesis procedure, done in the first two trimesters of pregnancy, can usually identify trisomy 8. Depending on the number of cells that are carefully studied, T8mS may also be identified.

In about 1–2% of CVS procedures that are performed, chromosomal mosaicism is found. However, this is confined to the placenta and does not represent the chromosomal status of the fetus. Additionally, a few babies reported in the literature were born with T8mS whose mothers had completely normal amniocentesis chromosome results during their pregnancies. For an unknown reason, amniocentesis may not provide the most accurate results with respect to T8mS. This makes it difficult when counseling and providing information to couples during pregnancy with respect to T8mS.

Individuals with T8mS can also be formally assessed by a medical geneticist and genetic counselor to aid in diagnosis, discussion of testing options, and interpretation of test results.

Treatment and management

There is no cure for T8mS. Therefore, treatments are based on a person's signs and symptoms.

A cleft palate can be repaired through stages with surgery, often first occurring in the first year of life. This usually requires a multidisciplinary team consisting of a plastic surgeon, pediatric dentist, pediatric anesthesiologist, nurses, dietician/feeding specialist, and social worker.

Hydronephrosis, if severe enough, can warrant surgery shortly after birth. The goal is to open the blocked area of the urinary tract and clear the obstruction into the kidney. Surgery may involve a team approach, including a pediatric urologist, pediatric nephrologist, nurses, and surgery technicians.

Congenital heart defects, if severe enough, can require surgery. Surgery varies depending on the problem and may involve a team, including a pediatric cardiologist, pediatric cardiovascular surgeon, pediatric anesthesiologist, pediatric cardiovascular radiologist, nurses, and surgery technicians.

Strabismus can often be treated with patching therapy or surgery. This may require a team involving a pediatric ophthalmologist, pediatric anesthesiologist, orthoptist, nurses, and surgery technicians. Severe corneal clouding may lead to vision problems, and can sometimes be treated with surgery, laser therapy, or corneal transplants.

Undescended testicles or testes can be brought down to the proper location in the scrotal sacs by a brief surgical procedure. This can involve a team, including a pediatric urologist, pediatric anesthesiologists, and nurses.

Some characteristics of T8mS do not necessitate treatment as they cause no medical harm. Examples of these include facial features, hand/foot creases, and some tissue and bone changes.

Mental delays and retardation may be assessed by a child development team or early childhood program. Extra assistance is sometimes available through early intervention programs and special education in schools. Social workers are useful to connect families to helpful resources.

Prognosis

People with T8mS have a prognosis that is entirely dependent upon the symptoms they experience. Someone born with a severe congenital heart defect may have a poorer prognosis for survival, growth, and development based on this. The average lifespan for someone with the T8mS is estimated to be near normal in the literature. Medical treatments and surgeries continue to offer hope.

Resources

WEBSITES

Chromosomal Mosaicism. Medical Genetics department at University of British Columbia. December 31, 2003 (March 15, 2005). <http://www.medgen.ubc.ca/wrobinson/mosaic/>.

Genetic Alliance. 2005 (March 15, 2005). <http://www.geneticalliance.org>.

The Human Genome Organization–Chromosome 8. (March 15, 2005.) <http://gdbwww.gdb.org/hugo/chr8/>.

ORGANIZATIONS

Chromosome Deletion Outreach, Inc. P.O. Box 724, Boca Raton, FL 33429-0724. Phone/Fax: (561) 395-4252. Email: [email protected]. <www.chromodisorder.org>.

UNIQUE Rare Chromosome Disorder Group. P.O. Box 2189, Caterham, Surrey CR3 5GN, UK. Phone/Fax: (44)(0)1883 330766. Email: [email protected]. <www.rarechromo.org>.

Deepti Babu, MS, CGC