Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

surgery as a final attempt to treat seizures, some physicians favor earlier surgery because this may prevent some irreversible damage to the brain (caused by the angiomas).

Standard glaucoma treatment, including medications and surgery, is used to treat people with this complication. This can often reduce the amount of vision loss.

There is no specific treatment for port-wine stains. Because they contain blood vessels, it could disrupt blood flow to remove or alter the birthmarks.

Prognosis

The prognosis for people with SWS is directly related to the amount of brain involvement for the leptomeningeal angiomas. For those individuals with smaller angiomas, prognosis is relatively good, especially if they do not have severe seizures or vision problems.

Resources

BOOKS

Charkins, Hope. Children with Facial Difference: A Parent’s Guide. Bethesda, MD: Woodbine House, 1996.

ORGANIZATIONS

The Sturge-Weber Foundation. PO Box 418, Mount Freedom, NJ 07970. (800) 627-5482 or (973) 895-4445. Fax: (973) 895-4846. swfoffice@aol.com. http://www.sturgeweber

.com/ .

WEBSITES

“Sturge-Weber Syndrome.” Family Village.http://www.familyvillage.wisc.edu/lib_stur.htm .

Sturge-Weber Syndrome Support Group of New Zealand.http://www.geocities.com/HotSprings/Spa/1563/ .

Deepti Babu, MS

Summitt syndrome see Carpenter syndrome

Surdicardiac syndrome see Jervell and

Lange-Nielsen syndrome

I Sutherland-Haan syndrome

Definition

Sutherland-Haan syndrome is an inherited X-linked disorder characterized by mental retardation, small head circumference, small testes, and spastic diplegia. Grant Sutherland and co-workers first described the syndrome in 1988. At present, it has only been fully described in one single, large, Australian family. Thus, it is unknown

K E Y T E R M S

Microcephaly—An abnormally small head.

Short stature—Shorter than normal height, can include dwarfism.

Small testes—Refers to the size of the male reproductive glands, located in the cavity of the scrotum.

Spasticity—Increased muscle tone, or stiffness, which leads to uncontrolled, awkward movements.

X-linked mental retardation—Subaverage general intellectual functioning that originates during the developmental period and is associated with impairment in adaptive behavior. Pertains to genes on the X chromosome.

if the disorder occurs worldwide or only in certain ethnic and racial groups. Since the responsible gene is located on the X chromosome, Sutherland-Haan syndrome is exclusively found in males. As the gene is unknown and only one family has been described (although there are families suspected of having Sutherland-Haan) the prevalence is unknown.

Description

Sutherland-Haan syndrome is among the group of genetic disorders known as X-linked mental retardation (XLMR) syndromes. Manifestations in males may be present prior to birth, as intrauterine growth appears to be mildly impaired since birth weight is below normal. Similarly, postnatal growth is slow with the head circumference being quite small (microcephaly) and height being rather short. Affected males exhibit poor feeding during infancy. Additionally, affected males have small testes after puberty.

The diagnosis is very difficult especially if there is no family history of mental retardation. If there is a family history of mental retardation and if the inheritance pattern is consistent with X-linkage, then the diagnosis is possible based on the presence of the above clinical findings and localization to Xp11.3 to Xq12.

Genetic profile

Sutherland-Haan syndrome is caused by an alteration in an unknown gene located in the pericentric region (area flanking the centromere) of the X chromosome. The altered gene in affected males is most likely inherited from a carrier mother. As males have only one X chromosome, a

syndrome Haan-Sutherland

Sutherland-Haan syndrome

Sutherland Haan syndrome is a form of mental retardation linked to a gene abnormality on the X chromosome. (Photo Researchers, Inc.)

mutation in an X-linked gene is fully expressed in males. On the other hand, as carrier females have a normal, second X-chromosome, they do not exhibit any of the phenotype associated with Sutherland-Haan syndrome.

Female carriers have a 50/50 chance of transmitting the altered gene to a daughter or a son. A son with the altered gene will be affected but will likely not reproduce.

Demographics

Only males are affected with Sutherland-Haan syndrome. Carrier females exhibit none of the phenotypic features. Although Sutherland-Haan has only been reported in a single Australian family, there is no reason to assume it is not present in other racial/ethnic groups.

Signs and symptoms

Evidence of Sutherland-Haan syndrome is present at birth as affected males have below normal birth weight.

This may reflect mildly impaired intrauterine growth. Postnatal growth is also slow. Head circumference is smaller than normal (microcephaly) and affected males tend to be short. Small testes are also present after puberty.

There are some somatic manifestations present in most of the males with Sutherland-Haan syndrome. These include mild to moderate spastic diplegia (increased muscular tone with exaggeration of tendon reflexes of the legs), upslanting of the eye openings, brachycephaly (disproportionate shortness of the head), and a thin body build. Additionally, a few of the affected males may have anal abnormalities.

Mental impairment is mild to moderate with IQ ranging from 43 to 60. One male was reported to have an IQ in the 63-83 range (borderline).

Diagnosis

The diagnosis of Sutherland-Haan can only be made on the basis of the clinical findings in the presence of a family history consistent with X-linked inheritance of mental retardation and segregation of X chromosome markers in Xp11.2-Xq12. Unfortunately, there are no laboratory or radiographic changes that are specific for Sutherland-Haan syndrome.

Renpenning syndrome, another X-linked mental retardation syndrome, also has microcephaly, short stature, small testes, and upslanting of the eye openings. Furthermore, this syndrome is localized to Xp11.2-p11.4, which overlaps with the localization of Sutherland-Haan. However, males with Renpenning syndrome lack spasticity of the legs, brachycephaly, and a thin appearance. It is possible these two syndromes have different mutations in the same gene.

Chudley-Lowry syndrome also has microcephaly, short stature, and small testes. However, males have distinct facial features, similar to those of XLMR-hypotonic facies, and obesity. As with Renpenning syndrome, this syndrome may result from a different mutation in the same gene responsible for Sutherland-Haan syndrome.

Two other X-linked mental retardation syndromes (XLMR-hypotonic facies and X-linked hereditary bullous dystrophy) have microcephaly, short stature, and small testes. However, these conditions have different somatic features and are not localized to Xp11.2-Xq12.

Treatment and management

There is neither treatment nor cure available for Sutherland-Haan syndrome as of early 2001. Early educational intervention is advised for affected males. Some affected males may require living in a more controlled environment outside the home.

Prognosis

Life threatening concerns usually have not been associated with Sutherland-Haan syndrome. However, two affected males were found to have anal abnormalities, which required some form of surgery.

Resources

PERIODICALS

Gedeon, A., J. Mulley, and E. Haan. “Gene Localisation for Sutherland-Haan Sydnrome (SHS:MIM309470).” American Journal of Medical Genetics 64 (1996): 78-79.

Sutherland, G.R., et al. “Linkage Studies with the Gene for an X-linked Sydnrome of Mental Retardation, Microcephaly, and Spastic Diplegia (MRX2).” American Journal of Medical Genetics 30 (1988): 493-508.

Charles E. Schwartz, PhD

Swedish-type porphyria see Porphyrias

Systemic elastorrhexis see Pseudoxanthoma elasticum

Systemic sclerosis see Scleroderma

syndrome Haan-Sutherland

Talipes see Clubfoot

I Tangier disease

Definition

Tangier disease is a rare autosomal recessive condition characterized by low levels of high density lipoprotein cholesterol (HDL-C) in the blood, accumulation of cholesterol in many organs of the body, and an increased risk of arteriosclerosis.

Description

Donald Fredrickson was the first to discover Tangier disease. He described this condition in 1961 in a five- year-old boy from Tangier Island who had large, yelloworange colored tonsils that were engorged with cholesterol. Subsequent tests on this boy and his sister found that they both had virtually no high density lipoprotein cholesterol (HDL-C) in their blood stream. Other symptoms of Tangier disease such as an enlarged spleen and liver, eye abnormalities, and neurological abnormalities were later discovered in others affected with this disease.

It was not until 1999 that the gene for Tangier disease, called the ABCA1 gene, was discovered. This gene is responsible for producing a protein that is involved in the pathway by which HDL removes cholesterol from the cells of the body and transports it to the liver where it is digested and removed from the body.

Cholesterol is transported through the body as part of lipoproteins. Low density lipoproteins (LDL) and high density lipoproteins (HDL) are two of the major cholesterol transporting lipoproteins. Cholesterol attached to LDL (LDL-C) is often called “bad” cholesterol since it can remain in the blood stream for a long time, and high

levels of LDL-C can increase the risk of clogging of the arteries (arteriosclerosis) and heart disease. Cholesterol attached to HDL is often called “good” cholesterol since it does not stay in the blood stream for a long period of time, and high levels are associated with a low risk of arteriosclerosis.

Research as of 2001 suggests that the ABCA1 protein helps to transport cholesterol found in the cell to the surface of the cell where it joins with a protein called ApoA-1 and forms an HDL-C complex. The HDL-C complex transports the cholesterol to the liver where the cholesterol is digested and removed from the body. This process normally prevents an excess accumulation of cholesterol in the cells of the body and can help to protect against arteriosclerosis.

Genetic profile

Changes in the ABCA1 gene, such as those found in Tangier disease, cause the gene to produce abnormal ABCA1 protein. The abnormal ABCA1 protein is less able to transport cholesterol to the surface of the cell, which results in an accumulation of cholesterol in the cell. The accumulation of cholesterol in the cells of the body causes most of the symptoms associated with Tangier disease. The decreased efficiency in removing cholesterol from the body can lead to an increased accumulation of cholesterol in the blood vessels, which can lead to a slightly increased risk of arteriosclerosis and ultimately an increased risk of heart attacks and strokes. The ABCA1 protein defect also results in decreased amounts of cholesterol available on the surface of the cell to bind to ApoA-1 and decreased cholesterol available to form HDL-C. This in turn results in the rapid degradation of ApoA-1 and reduced levels of ApoA-1 and HDL-C in the bloodstream. It also leads to lower levels of LDL-C in the blood.

The ABCA1 gene is found on chromosome 9. Since we inherit one chromosome 9 from our mother and one chromosome 9 from our father, we also

Tangier disease

disease Tangier

TAR syndrome

PERIODICALS

Brooks-Wilson, A., et al. “Mutations in ABCA1 in Tangier Disease and Familial High-density Lipoprotein Deficiency.” Nature Genetics 22, no. 4 (August 1999): 336-345.

Oram, John. “Tangier Disease and ABCA1.” Biochimica et Biophysica Acta 1529 (2000): 321-330.

ORGANIZATIONS

National Tay-Sachs and Allied Diseases Association. 2001 Beacon St., Suite 204, Brighton, MA 02135. (800) 9068723. ntasd-Boston@worldnet.att.net. http://www.ntsad

.org .

WEBSITES

“High Density Lipoprotein Deficiency, Tangier Type 1; HDLDT1.” Online Mendelian Inheritance in Man.

http://www. ncbi . nlm . nih . gov/entrez/dispomim

.cgi?id 271900 (December 8, 1999).

Lisa Maria Andres, MS, CGC

I TAR syndrome

Definition

Thrombocytopenia-absent radius (TAR) syndrome is a rare condition that is apparent at birth. Affected infants are born with incomplete or missing forearms. Typically, the bone on the thumb side of the forearm (radius) is absent, but other bones may be missing or abnormally formed. TAR syndrome also causes life-threatening bleeding episodes due to low levels of platelets in the blood (thrombocytopenia). It is inherited in an autosomal recessive manner.

Description

Dr. S. Shaw first wrote about two siblings (a brother and a sister) with missing forearms and bleeding problems in 1956. Thirteen years later, Dr. Judith Hall gave the name and acronym of TAR syndrome to the disorder. She described three families containing nine individuals. TAR syndrome has also been called the tetraphocomeliathrombocytopenia syndrome.

The forearm is comprised of two bones. The radius is the long bone on the thumb side of the forearm. The ulna is the long bone on the little finger side. In TAR syndrome, the radius is missing on each forearm. Many times the ulna may also be missing or shorter than normal.

As these bone deficiencies are quite obvious at birth, the forearms will look very short. In fact, the hand looks as if it comes directly from the elbow. In more severe cases, the bone of the upper arm is also missing, with the

Absence of the radius bone (that found in the forearm) is a primary indication of TAR syndrome. This infant is missing both radius bones resuling in shortened arms. The bruising on the body results from thrombocytopenia, low blood platelet count, which impairs the blood clotting process.

(Greenwood Genetic Center)

hand connected to the shoulder. Approximately 50% of the time there are other skeletal abnormalities, particularly in the lower limbs.

Each individual seems to be affected somewhat differently. For instance, some individuals with TAR syndrome might have one arm longer than the other arm; another might have both arms short, and bones missing in the feet; a third person might have all four limbs severely affected. The one constant feature is the absence of the radius bone. The forearm defects cause the hands to be bent inwards towards the body. However, the four fingers and thumb usually look normal.

The other main feature of the syndrome is thrombocytopenia. Thrombocytopenia means abnormally low levels of platelets in the blood. Platelets are made from cells called megakaryocytes. The megakaryocytes are

formed in the red bone marrow, lungs and spleen. In TAR syndrome, the megakaryoctyes are either absent, decreased in number or not formed properly. Therefore, the platelets are not properly made. The exact reason remains unknown.

When injury occurs, platelets are needed so that the blood can clot. The process is called blood coagulation. The platelets help initiate this process by attaching to the injured tissue, and clumping together, almost like a temporary patch. The platelets then release an enzyme called thromboplastin. Thromplastin acts to cleave a particle called fibrinogen (also in the blood) to fibrin. Fibrin is a hard substance that attaches to the injured area, and forms a meshwork (a blood clot). Along with other clotting factors, this permanently stops the bleeding.

In TAR syndrome, the normal process of making platelets is defective. The effect of this is excessive bleeding and bruising. These individuals have frequent nosebleeds and their skin bruises more easily. The platelet problem makes them more prone to bleeding inside the body, such as in the kidney or lungs. Bleeding can also occur inside the brain (intracranial hemorrhage), and be so severe that these infants die from the internal bleeding.

Genetic profile

There have been numerous instances of siblings, each with TAR syndrome. The parents were not affected. A few families have also been seen where the parents were said to be closely related (i.e. may have shared the same altered gene within the family). For these reasons, TAR syndrome is most likely an autosomal recessive disorder. Autosomal means that both males and females can have the condition. Recessive means that both parents would be carriers of a single copy of the responsible gene. Autosomal recessive disorders occur when a person inherits a particular pair of genes which do not work correctly. The chance that this would happen to children of carrier parents is 25% (1 in 4) for each pregnancy.

It is known that the limbs (arms, legs), the heart and the precursors of the blood system form between the fourth and eighth week of pregnancy. The birth defects seen in TAR syndrome must occur during this crucial period of development. As of 2001, the genetic cause remains unknown.

Demographics

TAR syndrome affects both males and females equally. It most likely occurs in every racial and ethnic group. It is estimated that one in every 250,000 infants are born with TAR syndrome. In all, more than 200 indi-

K E Y T E R M S

Cordocentesis—A prenatal diagnostic test, usually done between 16-30 weeks of gestation. Using ultrasound guidance, a thin needle is introduced through the abdomen into the amniotic sac. A blood sample is taken directly from the umbilical cord. Tests can then be done on the blood sample.

Intracranial hemorrhage—Abnormal bleeding within the space of the skull and brain.

Tetralogy of Fallot—A congenital heart defect consisting of four (tetralogy) associated abnormalities: ventricular septal defect (VSD—hole in the wall separating the right and left ventricles); pulmonic stenosis (obstructed blood flow to the lungs); the aorta “overrides” the ventricular septal defect; and thickening (hypertrophy) of the right ventricle.

Tetraphocomelia—Absence of all, or a portion of, all four limbs. The hands or feet may be attached directly to the trunk.

Thalidomide—A mild sedative that is teratogenic, causing limb, neurologic, and other birth defects in infants exposed during pregnancy. Women used thalidomide (early in pregnancy) in Europe and in other countries between 1957 and 1961. It is still available in many places, including the United States, for specific medical uses (leprosy, AIDS, cancer).

viduals with this disorder have been described in the medical literature.

Signs and symptoms

Aside from the limb deficiencies and the thrombocytopenia, the heart can also be affected. Around one-third of these infants are born with heart defects. These are usually found at birth. The heart problems include holes in the atrial chamber of the heart (atrial septal defect) and tetralogy of Fallot. The name tetralogy of Fallot means there are four different defects of the heart. Because of the high risk for excessive bleeding to occur, these infants are not good candidates for heart surgery. Some of them have died from heart failure.

Diagnosis

Diagnosis of TAR syndrome is made with the use of x ray of the bones and by testing for low platelet levels in

syndrome TAR

the blood at birth. TAR syndrome can be diagnosed during pregnancy. By using ultrasound (sound waves) at around 16-20 weeks of pregnancy, the shortening of the arms can be seen. A second test is then done called cordocentesis. In this procedure, using ultrasound guidance, a thin needle is introduced through the mother’s abdomen into the amniotic sac. A blood sample is taken directly from the umbilical cord. With this blood sample, a count of the platelets can be done. If the platelet count is low, along with the short arms (absent radii), the diagnosis of TAR syndrome is made.

Prognosis

About 40% of these individuals die in infancy, usually due to severe bleeding episodes. Cow’s milk allergy or intolerance is a common problem. Stomach infections seem particularly threatening to these infants, and can also trigger the bleeding episodes. The thrombocytopenia is treated with platelet transfusions, which may or may not control the bleeding, and death may occur.

The thrombocytopenia seen in TAR syndrome does improve with age. If these individuals survive the first

two years of life, they appear to have a normal life span. However, the easy bruising continues throughout life. Many females with TAR syndrome also have abnormal menstrual periods, possibly related to the thrombocytopenia.

Surgery is sometimes done in an attempt to straighten and improve the use of their hands. They may wear corrective braces for the forearms. Many of these individuals develop arthritis, especially of the wrists and knees as they get older. This may further limit the use of their hands and legs. However, most individuals with TAR syndrome learn to adapt well to their disability, and lead productive lives.

Resources

PERIODICALS

Hall, Judith. “Thrombocytopenia with Absent Radius (TAR).” Medicine (1969): 411-439.

ORGANIZATIONS

T.A.R.S.A. Thrombocytopenia Abset Radius Syndrome Association. 212 Sherwood Drive, Linwood, NJ 083247658. (609) 927-0418.

WEBSITES

The Association for Children with Hand or Arm Deficiency.http://www.reach.org.uk.htm .

Kevin M. Sweet, MS, CGC

I Tay-Sachs disease

Definition

Tay-Sachs disease is a genetic disorder caused by a missing enzyme that results in the accumulation of a fatty substance in the nervous system. This results in disability and death.

Description

Gangliosides are a fatty substance necessary for the proper development of the brain and nerve cells (nervous system). Under normal conditions, gangliosides are continuously broken down, so that an appropriate balance is maintained. In Tay-Sachs disease, the enzyme necessary for removing excess gangliosides is missing. This allows gangliosides to accumulate throughout the brain, and is responsible for the disability associated with the disease.

Demographics

Tay-Sachs disease is particularly common among Jewish people of Eastern European and Russian (Ashkenazi) origin. About one out of every 3,600 babies born to Ashkenazi Jewish couples will have the disease. Tay-Sachs is also more common among certain FrenchCanadian and Cajun French families.

Genetic profile

Tay-Sachs is caused by a defective gene. Genes are located on chromosomes, and serve to direct specific development/processes within the body. The genetic defect in Tay-Sachs disease results in the lack of an enzyme called hexosaminidase A. Without this enzyme, gangliosides cannot be degraded. They build up within the brain, interfering with nerve functioning. Because it is a recessive disorder, only people who receive two defective genes (one from the mother and one from the father) will actually have the disease. People who have only one defective gene and one normal gene are called carriers. They carry the defective gene and thus the possibility of passing the gene and/or the disease onto their offspring.

K E Y T E R M S

Ganglioside—A fatty (lipid) substance found within the brain and nerve cells.

When a carrier and a non-carrier have children, none of their children will actually have Tay-Sachs. It is likely that 50% of their children will be carriers themselves. When two carriers have children, their children have a 25% chance of having normal genes, a 50% chance of being carriers of the defective gene, and a 25% chance of having two defective genes. The two defective genes cause the disease itself.

Signs and symptoms

Classic Tay-Sachs disease strikes infants around the age of six months. Up until this age, the baby will appear to be developing normally. When Tay-Sachs begins to show itself, the baby will stop interacting with other people, and develop a staring gaze. Normal levels of noise will startle the baby to an abnormal degree. By about one year of age, the baby will have very weak, floppy muscles, and may be completely blind. The head will be quite large. Patients also present with loss of peripheral (side) vision, inability to breathe and swallow, and paralysis as the disorder progresses. Seizures become a problem between ages one and two, and the baby usually dies by about age four.

A few variations from this classical progression of Tay-Sachs disease are possible:

•Juvenile hexosaminidase A deficiency. Symptoms appear between ages two and five; the disease progresses more slowly, with death by about 15 years of age.

•Chronic hexosaminidase A deficiency. Symptoms may begin around age five, or may not occur until age 20-30. The disease is milder. Speech becomes slurred. The individual may have difficulty walking due to weakness, muscle cramps, and decreased coordination of movements. Some individuals develop mental illness. Many have changes in intellect, hearing, or vision.

Diagnosis

Examination of the eyes of a child with Tay-Sachs disease will reveal a very characteristic cherry-red spot at the back of the eye (in an area called the retina). Tests to determine the presence and quantity of hexosaminidase A can be performed on the blood, specially treated skin cells, or white blood cells. A carrier will have about half

disease Sachs-Tay