About radial aplasia-thrombocytopenia syndrome

What is radial aplasia-thrombocytopenia syndrome?

Thrombocytopenia-absent radius (TAR) syndrome is a rare disorder that is present at birth (congenital). It is characterized by low levels of platelets in the blood (thrombocytopenia) and absence (aplasia) of the long, thin bones of the forearms (radii). Other abnormalities are often present including additional skeletal defects such as absence or underdevelopment of the other bone of the forearm (ulna), structural malformations of the heart (congenital heart defects), and kidney (renal) defects. Affected individuals may be abnormally short for their age (short stature) and exhibit cow's milk intolerance. TAR syndrome is inherited as an autosomal recessive genetic disorder and caused by deletion and/or mutations in the RBM8A gene.

What are the symptoms for radial aplasia-thrombocytopenia syndrome?

TAR syndrome can potentially affect multiple systems of the body, but it is especially associated with blood (hematological) and bone (skeletal) abnormalities. The two main findings are thrombocytopenia and radial aplasia. A variety of additional symptoms also occur. The specific symptoms vary from patient to patient. Affected individuals will not have all of the symptoms listed below. Some symptoms improve over time and may cause little or no problems in adulthood. Most affected individuals have normal intelligence, are able live independently, and many have married and have had their own children.

Approximately 90 percent of affected individuals develop symptoms related to low levels of the platelets in the blood during the first year of life. Platelets are specialized blood cells that clump together to form clots to stop bleeding. In TAR syndrome certain specialized cells in the bone marrow known as megakaryocytes are defective or improperly developed (hypoplastic). Megakaryocytes normally develop into platelets. The normal maturation of megakaryocytes into platelets does not occur in individuals with TAR syndrome, causing the low levels of platelets, which may be referred to as (hypomegakaryocytic thrombocytopenia). The exact reason why megakaryocytes fail to develop into platelets is unknown.

In individuals with TAR syndrome, the level of platelets in the blood goes up and down. Episodes of thrombocytopenia are most frequent during the first two years of life. Episodes may be preceded or triggered by certain infections, such as viral illnesses (particularly digestive [gastrointestinal] illnesses), surgery, stress, or other factors, such as intolerance to cow’s milk (see below).

Low platelet levels can result in severe Bleeding episodes (hemorrhaging). Specific symptoms of thrombocytopenia include frequent nosebleeds or gastrointestinal bleeding, which can result in the Vomiting of blood (hematemesis) or bloody stools. In addition, affected individuals may develop Bleeding (hemorrhages) within skin (dermal) layers or layers below the mucous membranes (submucosal), resulting in easy Bruising (ecchymoses) and/or the appearance of pinpoint-sized, purplish or reddish spots on the skin (petechiae). In severely affected patients, Bleeding episodes, particularly in the brain (intracranial hemorrhaging), may lead to potentially life-threatening complications during infancy. In addition, Intellectual disability has been reported in some individuals who had a history of intracranial hemorrhaging. Otherwise, intelligence in individuals with TAR syndrome is usually unaffected.

As mentioned above, thrombocytopenia typically is most severe during the first year of life. By adulthood, platelet levels may improve to almost normal ranges. Therefore, adults may have few associated symptoms; however, affected women may have unusually heavy or prolonged menstrual periods (menorrhagia).

In addition to platelets, the two other main blood cell lines (red and white cells) may also be affected. Red blood cells deliver oxygen to the body and white blood cells help in fighting off infections. Low levels of circulating red cells (anemia) may occur. Anemia is associated with fatigue, pale skin, and weakness. Some affected children may have an excessive amount of white blood cells called a “leukemoid reaction”. This occurs in infants with extremely low platelet levels. There may also be enlargement of the liver and spleen (hepatosplenomegaly). In some patients, increased levels of a specific type of white blood cell called an eosinophil (eosinophilia) may also occur. The cause of eosinophilia is not known. It is often associated with allergy or asthma and may occur in children with TAR syndrome who have cow’s milk intolerance.

A variety of Skeletal abnormalities occur in individuals with TAR syndrome. The characteristic finding is absence (aplasia) of one of the bones of the forearm (radius). The radii of both arms are affected (bilateral). The radius is a long thin bone that extends from the elbow to the thumb side of the wrist. The thumbs are present in individuals with TAR syndrome, a finding that distinguishes it from other disorders involving radii. The hands, fingers and thumbs are almost always unaffected, although the fingers may be abnormally short.

Additional Skeletal abnormalities may also occur including underdevelopment or absence of the other bone of the forearm, the ulna. Sometimes the long bone of the upper arm (humerus), which extends from the shoulder to the elbow, may be underdeveloped. In some cases, the shoulder girdle may also be underdeveloped and affected individuals may have reduced upper body strength. In severe cases, the arms may be missing and the hands may be joined to the trunk by small, irregularly-shaped bone (phocomelia).

In some patients, the lower limbs may be involved. The severity may range from barely noticeable changes to significant malformations. Affected individuals may exhibit abnormalities of the knees including a loose kneecap that does not slide properly within its groove (patellar subluxation) and can potentially slide completely out of the socket (dislocate), absence of the knee cap (patella) or, rarely, the bones of the knees may be fused together. Dislocation of the hip, in which the head of the long bone of the upper leg (femur) does not fit properly into its socket in the hip, may also occur. Additional lower limb abnormalities often occur including improper inward rotation of the long bones of the legs (femoral and tibial torsion), bowing of the legs, and abnormalities affecting the feet and toes. Lower limb abnormalities can potentially affect the ability to walk (mobility). Most individuals with severe involvement of the upper limbs are more likely to have abnormalities of the lower limbs.

In addition, cow’s milk intolerance or allergy has frequently been reported in association with TAR syndrome. In these children, introduction of cow’s milk to the diet may precipitate thrombocytopenic, eosinophilic, and/or “leukemoid” episodes (see above). Cow’s milk intolerance can also cause a variety of gastrointestinal symptoms including nausea, vomiting, diarrhea, and failure to gain weight and grow at the expected rate (failure to thrive).

Approximately one third of affected infants also have structural malformations of the heart (congenital heart defects). Such cardiac defects may include an abnormal opening in the fibrous partition (septum) that divides the upper chambers of the heart (atrial septal defect) or a malformation known as tetralogy of Fallot. The latter describes a combination of heart defects, including abnormal narrowing (stenosis) of the opening between the pulmonary artery (which carries blood to the lungs) and the lower right chamber (ventricle) of the heart, an abnormal opening in the partition between the lower chambers of the heart (ventricular septal defect); displacement of the major artery that transports oxygen-rich blood to most of the body (i.e., aorta); and enlargement of the right ventricle (hypertrophy).

Some individuals with TAR syndrome may exhibit Short stature. A variety of additional Physical abnormalities have been reported to be associated with TAR syndrome including an abnormally Small jaw (micrognathia), incomplete closure of the roof of the mouth (cleft palate), one or more pink or dark red irregularly shaped patches of skin (hemangiomas) on the face caused by dense collections of small blood vessels (capillaries), or minor abnormalities affecting the spine and ribs. Kidney (renal) defects may also be present, such as a malformation in which the two kidneys are abnormally joined at the base (horseshoe kidney) as well as underdevelopment (hypoplasia) and improper function of the kidneys. Some of these findings have only occurred in a few reported patients and researchers do not know whether these are coincidental occurrences or whether individuals with TAR syndrome have a greater risk of developing these manifestations.

What are the causes for radial aplasia-thrombocytopenia syndrome?

TAR syndrome is inherited as an autosomal recessive genetic disorder and caused by two different types of mutations in the RBM8A gene.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disorder but usually will not show symptoms. However, reports have been published that describe an affected child born to an affected parent. 

Some researchers suggest that TAR syndrome may result from mutations of different disease genes (genetic heterogeneity). Further research is required to determine the underlying genetic cause or causes of the disorder.

What are the treatments for radial aplasia-thrombocytopenia syndrome?

The treatment of TAR syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians, surgeons, physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists), specialists in the study of the blood and blood-forming tissues (hematologists), physicians who specialize in heart disease (cardiologists), and/or other health care professionals.

Physicians may recommend preventive measures to help affected infants and children avoid infection, stress, or other factors that may precipitate thrombocytopenia. In addition, experts indicate that cow’s milk should be avoided, since its introduction may precipitate thrombocytopenic, eosinophilic, or “leukemoid” episodes. 

Management of the disorder may include ongoing monitoring and supportive hematologic measures as required, such as platelet transfusions or transfusions with whole blood products. In some cases, the use of certain medications or other measures may be recommended to help prevent or treat hematologic complications. As noted above, thrombocytopenia typically improves with age.

In individuals with TAR syndrome, various orthopedic techniques may also be recommended, such as splints, corrective braces, and/or certain surgical measures. In some cases, the use of adaptive and/or artificial devices (prosthetics) and mobility aids, such as wheelchairs or motorized carts, may also be beneficial.

For affected individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.

Early intervention may be important to ensure that children with TAR syndrome reach their potential. Special services that may be beneficial include special education, physical therapy, and/or other medical, social, or vocational services.

Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.

What are the risk factors for radial aplasia-thrombocytopenia syndrome?

The risk for two carrier parents to both pass the defective gene and have an affected child is theoretically 25% with each pregnancy, but because the RBM8A gene deletion associated with TAR syndrome is often not inherited, but occurs as a new mutation in about 25% of those affected, the risk for affected sibs is lower. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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